Pyrazolo[3.4-B]pyrazine compounds as p38 modulators and methods of use as anti-inflamatory agents

ABSTRACT

The present invention comprises a new class of compounds useful for the prophylaxis and treatment of protein kinase mediated diseases, including inflammation and related conditions. The compounds have a general Formula I 
                         
wherein A 1 , B, R 1 , R 2 , R 3 , R 4 , R 5  and n are defined herein. The invention also comprises pharmaceutical compositions including one or more compounds of Formula I, uses of such compounds and compositions for treatment of p38 map kinase mediated diseases including rheumatoid arthritis, psoriasis, chronic obstructive pulmonary disease, pain and other inflammatory disorders, as well as intermediates and processes useful for the preparation of compounds of Formula I.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/070,394, filed Mar. 21, 2008, which is herebyincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates generally to the field of pharmaceutical agentsand, more specifically, to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treat variousdisorders, including TNF-α, IL-β, IL-6 and/or IL-8 mediated diseases andother maladies, such as inflammation and pain. The invention alsorelates to intermediates and processes useful in the preparation of suchcompounds.

BACKGROUND OF THE INVENTION

Protein kinases represent a large family of enzymes, which catalyze thephosphorylation of target protein substrates. The phosphorylation is atransfer reaction of a phosphate group from ATP to the proteinsubstrate. Common points of attachment for the phosphate group to theprotein substrate include, for example, a tyrosine, serine or threonineresidue. Protein tyrosine kinases (PTKs) are enzymes, which catalyze thephosphorylation of specific tyrosine residues in cellular proteins.Examples of kinases in the protein kinase family include, withoutlimitation, abl, Akt, bcr-abl, Blk, Brk, Btk, c-kit, c-Met, c-src,c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1,FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R,INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie,tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellularprocesses, protein kinases have emerged as important therapeutictargets.

Protein kinases play a central role in the regulation and maintenance ofa wide variety of cellular processes and cellular function. For example,kinase activity acts as molecular switches regulating inflammatorycytokine production via various pathways. Uncontrolled or excessivecytokine production has been observed in many disease states, andparticularly in those related to inflammation.

The p38 protein kinase has been reported to be involved in theregulation of inflammatory cytokines. Interleukin-1 (IL-1) and TumorNecrosis Factor α (also referred to herein as TNF-α or TNF) arepro-inflammatory cytokines secreted by a variety of cells, includingmonocytes and macrophages, in response to many inflammatory stimuli(e.g., lipopolysaccharide (LPS)) or external cellular stress (e.g.,osmotic shock and peroxide).

Elevated levels of TNF-α over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis (RA); osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease (IBD); adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis;ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscledegeneration; cachexia; Reiter's syndrome; type II diabetes; boneresorption diseases; graft vs. host reaction; ischemia reperfusioninjury; atherosclerosis; brain trauma; multiple sclerosis; cerebralmalaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgiasdue to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza,adenovirus, the herpes viruses (including HSV-1, HSV-2), and herpeszoster are also exacerbated by TNF-α.

TNF-α has been reported to play a role in head trauma, stroke, andischemia. For instance, in animal models of head trauma (rat), TNF-αlevels increased in the contused hemisphere (Shohami et al., J. Cereb.Blood Flow Metab. 14:615 (1994)). In a rat model of ischemia wherein themiddle cerebral artery was occluded, the levels of TNF-α mRNA of TNF-αincreased (Feurstein et al., Neurosci. Lett., 164:125 (1993)).Administration of TNF-α into the rat cortex has been reported to resultin significant neutrophil accumulation in capillaries and adherence insmall blood vessels. TNF-α promotes the infiltration of other cytokines(IL-1β, IL-6) and also chemokines, which promote neutrophil infiltrationinto the infarct area (Feurstein, Stroke 25:1481 (1994)).

TNF-α appears to play a role in promoting certain viral life cycles anddisease states associated therewith. For instance, TNF-α secreted bymonocytes induced elevated levels of HIV expression in a chronicallyinfected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)).Landevirta et al., (Am. J. Med. 85:289 (1988)) discussed the role ofTNF-α in the HIV associated states of cachexia and muscle degradation.

TNF-α is upstream in the cytokine cascade of inflammation. As a result,elevated levels of TNF-α may lead to elevated levels of otherinflammatory and proinflammatory cytokines, such as IL-1, IL-6, andIL-8. Elevated levels of IL-1 over basal levels have been implicated inmediating or exacerbating a number of disease states includingrheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; goutyarthritis; inflammatory bowel disease; adult respiratory distresssyndrome (ARDS); psoriasis; Crohn's disease; ulcerative colitis;anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type IIdiabetes; bone resorption diseases; ischemia reperfusion injury;atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock;and toxic shock syndrome. Viruses sensitive to TNF-α inhibition, e.g.,HIV-1, HIV-2, HIV-3, are also affected by IL-1.

Antagonism of TNF-α has been reported to be beneficial for treatinguveitis (Reiff et al, A&R 44:141-145 (2001)); Sepsis (Abraham, Lancet,351:929 (1998)); Systemic Lupus Erythrematosis (SLE) (Aringer, A&R,50:3161 (2004)); Graft vs Host Disease (Couriel, Curr. Opinion Oncology,12:582 (2000)); Polymyositis and Dermatomyositis (Labiache,Rheumatology, 43:531 (2004)); Type II diabetes (Ruan, Cytokine GFReview, 14:447 (2003)); Sjogren's disease (Marriette, A&R, 50:1270(2004)), Sarcoidosis (Roberts, Chest, 124:2028 (2003)); Wegener'sgranulomatosis (WGET, New England J. Med., 352:351 (2005)) and post MIcardiac dysfunction (Sugano et al, Mol. Cell Bioch., 266:127 (2004)). Inaddition, TNF-α has been reported to play a role in SAPHO, periodicfever, relapsing polychrondritis, multicentric reticulohistiocytosis,macrophage activation syndrome, Hyper IgD syndrome, familial Hibernianfever, Pyoderma gangrenosum, Cochleovestibular disorders, Cicatricalpemphigoid, Herniated intervertebral disc diseases, amyloidosis, CINCAsyndrome, myelodisplastic syndrome, alcoholic hepatitis, andendometriosis. Finally, indications which have already been approved fortreatment with a therapeutic agent which modulates TNF-α levels in theplasma, and/or other pro-inflammatory cytokines, include withoutlimitation, inflammatory bowel disease (IBD), psoriatis arthritis,ankylosing spondylitis and juvenile RA.

TNF-α and IL-1 appear to play a role in pancreatic β cell destructionand diabetes. Pancreatic β cells produce insulin which helps mediateblood glucose homeostasis. Deterioration of pancreatic β cells oftenaccompanies type I diabetes. Pancreatic β cell functional abnormalitiesmay occur in patients with type II diabetes. Type II diabetes ischaracterized by a functional resistance to insulin. Further, type IIdiabetes is also often accompanied by elevated levels of plasma glucagonand increased rates of hepatic glucose production. Glucagon is aregulatory hormone that attenuates liver gluconeogenesis inhibition byinsulin. Glucagon receptors have been found in the liver, kidney andadipose tissue. Thus, glucagon antagonists are useful for attenuatingplasma glucose levels (WO 97/16442, incorporated herein by reference inits entirety). By antagonizing the glucagon receptors, it is thoughtthat insulin responsiveness in the liver will improve, therebydecreasing gluconeogenesis and lowering the rate of hepatic glucoseproduction. Elevation of glucose levels along with the reducedexpression of IL-1Ra, an antagonist of IL-1 signaling, leads to impairedinsulin secretion, decreased cell proliferation and apoptosis. Inhibitonof IL-1 action has been shown to improve glycemia, b-cell secretoryfunction and reduce markers of systemic inflammation (Larsen, NewEngland J. Med., 356: 1517 (2007).

In rheumatoid arthritis models in animals, multiple intra-articularinjections of IL-1 led to an acute and destructive form of arthritis(Chandrasekhar et al., Clinical Immunol Immunopathol., 55:382 (1990)).In studies using cultured rheumatoid synovial cells, IL-1 is a morepotent inducer of stromelysin than is TNF-α (Firestein, Am. J. Pathol.,140:1309 (1992)). At sites of local injection, neutrophil, lymphocyte,and monocyte emigration has been observed. The emigration is attributedto the induction of chemokines (e.g., IL-8), and the up-regulation ofadhesion molecules (Dinarello, Eur. Cytokine Netw., 5:517-531 (1994)).

IL-1 also appears to play a role in promoting certain viral life cycles.For example, cytokine-induced increase of HIV expression in achronically infected macrophage line has been associated with aconcomitant and selective increase in IL-1 production (Folks et al., J.Immunol., 136:40 (1986)). Beutler et al. (J. Immunol., 135:3969 (1985))discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J.Med., 308:553 (1983)) discussed the role of IL-1 in muscle degeneration.

In rheumatoid arthritis (RA), both IL-1 and TNF-α induce synoviocytesand chondrocytes to produce collagenase and neutral proteases, whichleads to tissue destruction within the arthritic joints. In an in-vivoanimal model of arthritis, i.e., collagen-induced arthritis (CIA) inrats and mice, intra-articular administration of TNF-α either prior toor after the induction of CIA led to an accelerated onset of arthritisand a more severe course of the disease (Brahn et al., LymphokineCytokine Res. 11:253 (1992); and Cooper, Clin. Exp. Immunol., 898:244(1992)). IL-1 and TNF-α have been implicated in pro-inflammatorymechanisms in many human diseases including inflammatory arthritis,inflammatory bowel disease sepsis syndrome and both acute and cheonisinflammation of many organs. (Vassali P., The Pathophysiology of TumorNecrosis Factors, Ann. Rev. Immunology 10: 411-452 (1992) and DinarelloC A, Biologic Basis for Interluekin-1 in disease, Blood, 87:2095-2147(1996)).

IL-6 also appears to play a role in, and therefore have applications to,pro-inflammatory and other malignant diseases. Particularly, deregulatedlevels of IL-6 are associated with various immunological diseases, suchas RA, systemic juvenile idiopathic arthritis (sJIA), polyarticular typeJIA, systemic lupus erythematosus (SLE), vasculitis syndrome, CastlemanDisease and Crohn's Disease; transplantation conditions such as acuterejection and graft-versus-host disease (GVHD); respiratory diseasessuch as interstitial pneumonia and bronchial; asthma; bone diseases suchas osteoporosis and Paget's disease, as well as various malignantdisease including multiple myeloma, renal cancer, prostate cancer,cardiac mixoma, Kaposis sarcoma, Mesothelioma, Malignant lymphoma, lungcancer and gastric cancer. (Nishimoto and Kishimoto, Review, 2: 619-625(2006)). It follows that the reduction and/or regulation of IL-6 levelsmay be useful for treatment of one or more of the above diseases.

IL-8 has been implicated in exacerbating and/or causing many diseasestates in which massive neutrophil infiltration into sites ofinflammation or injury (e.g., ischemia) is mediated by the chemotacticnature of IL-8, including, but not limited to, the following: asthma,inflammatory bowel disease, psoriasis, adult respiratory distresssyndrome, cardiac and renal reperfusion injury, thrombosis andglomerulonephritis. In addition to the chemotaxis effect on neutrophils,IL-8 also has the ability to activate neutrophils. Thus, reduction inIL-8 levels may lead to diminished neutrophil infiltration.

The role and activity of the p38 protein in RA and otherpro-inflammatory cytokine mediated diseases and conditions are becomingbetter understood. For example, Korb et al., Arthritis and Rheumatism,54: 2745-2756 (2006) describes the activation of the p38 alpha (p38α)and p38 gamma (p38γ) and the role which these two isoforms play in thedevelopment and progression of RA. Korb further describes thecorrelation between expression of p38 and the incidence of CRP in RA.Korb has found that the expression of these isoforms dominate inpatients with chronic inflammation and, therefore, concludes thateffective strategies to inhibit p38 kinase should aim to specificallytarget either or both of the isoforms. Medicherla et al., J.Pharmacology and Experimental Therapeutics, 318, 132-141 (2006) andNishikawa et al., Arthritis & Rheumatism, 48, 2670-2681 (2003) describeresults of an in-vivo collegan-induced arthritis (CIA) model in the ratand mouse. More specifically, they report that, in both animals,inhibition of p38α activity and related signaling improved clinicalscore and reversed bone and cartilage destruction. Ferrari,Cardiovascular Research 37:554 (1998) and Jacobsson et al., J Rheum.32:1213 (2005) describe how pro-inflammatory cytokines, such as TNF andIL-1, play a role in cadiovascular disease. More specifically, they havefound that blocking or reducing the levels of TNF-α have a protectiveeffect, and reduce the incidence of cardiovascular disease in RApatients. Behr et al., Circulation, 104, 1292 (2001) describes theability and efficacy of a p38 kinase inhibitor in treating hypertensivecardiac hypertrophy.

Several approaches have been taken to block the effect of TNF-α. Oneapproach involves using soluble receptors for TNF-α (e.g., TNFR-55 orTNFR-75), which have demonstrated efficacy in animal models ofTNF-α-mediated disease states. A second approach to neutralizing TNF-αusing a monoclonal antibody specific to TNF-α, cA2, has demonstratedimprovement in swollen joint count in a Phase II human trial ofrheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.195-223 (1995)). These approaches block the effects of TNF-α and IL-1 byeither protein sequestration or receptor antagonism.

Yet another approach to block the effect of TNF-α, and otherpro-inflammatory cytokines, has been to modulate the activity of the p38kinase enzyme. For example, the PCT publication, WO 04/010995, publishedon Feb. 5, 2004, describes fused heteroaryl derivatives for use as p38kinase inhibitors in the treatment of I.A. and rheumatoid arthritis; PCTpublication, WO 2005/009937, published on Feb. 3, 2005, describes5-membered heterocycle-based p38 kinase inhibitors; U.S. Pat. No.6,635,644, issued Oct. 21, 2003, describes fused nitrogen-containingbicyclic ring systems as p38 inhibitors; and U.S. Pat. No. 6,794,380,issued Sep. 21, 2004, describes amide derivatives as p38 inhibitors.Despite the ongoing efforts, there needs to be effectiveanti-inflammatory agents which regulate the production ofpro-inflammatory cytokines, including TNF-α, IL-1β, IL-6 and/or IL-8.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful in theprophylaxis and treatment of diseases mediated by pro-inflammatorycytokines, such as TNF-α, IL-1β, IL-6 and/or IL-8. The compounds,including stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts, derivatives or prodrugs thereof, are generally definedby Formula I

wherein A¹, B, R¹, R², R³, R⁴, R⁵ and n are as described below. Theinvention also provides procedures for making compounds of Formula I,compounds of Formula II, and intermediates useful in such procedures.

The compounds provided by the invention are capable of modulating thep38 kinase protein. To this end, the compounds of the invention areuseful for regulating the levels of pro-inflammatory cyctokines and fortherapeutic, prophylactic, acute and/or chronic treatment of TNF-α,IL-1β, IL-6 and/or IL-8 mediated diseases, such as those describedherein. For example, the compounds are useful for the prophylaxis andtreatment of RA, pain, and other conditions involving inflammation. Inanother embodiment, the invention provides pharmaceutical compositions,also commonly referred to as “medicaments”, comprising one or more ofthe compounds of the invention in combination with one or morepharmaceutically acceptable carrier(s) or excipient(s). Suchpharmaceutical compositions are useful to attenuate, alleviate, or treatp38 kinase-mediated disorders through inhibition of the activity of thep38 kinase enzyme.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are defined by general Formula I:

wherein

A¹ is CR⁴ or N;

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with 1-5 substituents of R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹;

R² is H, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁹;

R³ is CN, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyland C₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁹;

each R⁴, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-5substituents of R⁹;

R⁵ is R⁷, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(NCN)R⁷, C(O)R⁸,C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)C(O)R⁸, OC(O)R⁸, COOR⁸,C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyloptionally comprising 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of NR⁸R⁹, NR⁹R⁹, OR⁸, SR⁸,OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹, COOR⁹, C(O)NR⁸R⁹,C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹, NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸),NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸, S(O)₂NR⁸R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ orR⁹;

R⁸ is a partially or fully saturated or fully unsaturated 3-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, andwherein each ring of said ring system is optionally substitutedindependently with 1-5 substituents of R⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹,COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹, NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹,S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or a partially or fully saturated or unsaturated5-6 membered ring of carbon atoms optionally including 1-3 heteroatomsselected from O, N, or S, and optionally substituted independently with1-3 substituents of R⁹;

alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from O, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0, 1 or 2.

In another embodiment, the compounds of Formula I include compoundswherein A¹ as CR⁴, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein wherein A¹ is CR⁴ and R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with 1-5substituents of R⁹; and

R² is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₁₀-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ as N, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is CR⁴ wherein R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein A¹ is CR⁴ wherein R⁴ is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, OH, NO₂, NH₂, CN, methyl,ethyl or propyl, in conjunction with any of the above or belowembodiments.

In another embodiment, related to the immediately preceedingembodiments, the compounds of Formula I include compounds wherein eachR⁴, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, related to the immediately preceedingembodiments, Formula I includes compounds wherein each R⁴,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —O—C₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl or the C₁₋₁₀-alkyl optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O, S or N—CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is S, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is N—CN, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I include compoundswherein B is O or S, in conjunction with any of the above or belowembodiments.

In another embodiment, related to the immediately preceedingembodiments, Formula I includes compounds wherein A¹ is CR⁴;

B is O;

R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,indolyl, indolinyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,benzimidazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently with1-3 substituents of R⁹;

R² is H, halo, haloalkyl or C₁₋₁₀-alkyl;

R³ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with 1-5substituents of R⁹;

R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, whereinthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹;

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

n is 0 or 1.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, pentyl, neopenyl, hexyl, cyclopropyl, cyclopentyl, cyclohexylor allyl, each of which is optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl,isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl, indolyl, indolinyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzimidazolyl,piperidinyl, pyranyl, cyclopropyl, cyclobutyl or cyclohexyl, each ofwhich is optionally substituted independently with 1-5 substituents ofR⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, tetrahydrofuryl, pyrrolyl,tetrahydropyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl,isothiazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl,thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl or isothiazolyl, each ofwhich is optionally substituted independently with one or moresubstituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, eachof which is optionally substituted independently with 1-5 substituentsof R⁹, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently with1-5 substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl or pyridyl, each of which is optionally substitutedindependently with one or more substituents of R⁹, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is phenyl, optionally substituted independently with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R¹ is thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl or isothiazolyl,each of which is optionally substituted independently with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₁₀-alkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, halo, haloalkyl or C₁₋₁₀-alkyl, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, halo, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R² is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R³ is CN, C(O)R², C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl and C₂₋₁₀-alkynyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R³ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl,isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentylor C₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R³ is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, pentyl or neopentyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, OH,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with 1-5substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—OC₂F₅, —O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, NO₂,NH₂, CN, OH or C₁₋₄-alkyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, —OCH₃,C₂F₅, —OC₂F₅, NO₂, NH₂, CN, OH, methyl, ethyl, or propyl, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is R⁷, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷, C(NCN)R⁷,C(O)R⁸, C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)C(O)R⁸, OC(O)R⁸,COOR⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷),NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸,NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, S(O)₂NR⁷R⁷,S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷ or NR⁷C(O)R⁸, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is C(O)NHC₁₋₆-alkyl, C(O)NHC₂₋₆-alkenyl, C(O)NHC₂₋₆-alkynyl,C(O)NHC₃₋₆-cycloalkyl, C(O)NHaryl, C(O)NHheteroaryl, NHC(O)C₁₋₆-alkyl,NHC(O)C₂₋₆-alkenyl, NHC(O)C₂₋₆-alkynyl, NHC(O)C₃₋₆-cycloalkyl,NHC(O)aryl or NHC(O)heteroaryl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁵ is C(O)NR⁷R⁷ or C(O)NR⁷R⁸, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I include compoundswherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I include compoundswherein

A¹ is CR⁴ or N;

B is O;

R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,indolyl, indolinyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,benzimidazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently with1-3 substituents of R⁹;

R² is H, halo, haloalkyl or C₁₋₁₀-alkyl;

R³ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅,—O—C₁₋₆-alkyl, —C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—C₁₋₄-alkyl-S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂,—C₁₋₄-alkyl-NH—C₁₋₆-alkyl, —C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN,C₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally substituted with 1-5substituents of R⁹;

R⁵ is NR⁷R⁷, NR⁷R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸,S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, whereinthe C₁₋₁₀-alkyl and C₃₋₁₀-cycloalkyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl; and

N is 0 or 1.

In another embodiment, the compounds of Formula I include compoundswherein

R¹ is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, oxazolinyl, isoxazolyl, isoxazolinyl,oxadiazolyl, isothiazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutylor cyclohexyl, each of which is optionally substituted independentlywith 1-3 substituents of R⁹;

R² is H, F, Cl, CF₃, methyl or ethyl;

R³ is CN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-;

each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, —NH—C₁₋₃-alkyl, NO₂, NH₂, OH, CN, methyl,ethyl propyl or isopropyl;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, wherein theC₁₋₆-alkyl and C₃₋₆-cycloalkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-3substituents of R⁹;

R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I include compoundswherein

R¹ is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl or isothiazolyl, eachof which is optionally substituted independently with 1-3 substituentsof R⁹;

R² is H, F, Cl, CF₃ or methyl;

R³ is C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₄-dialkylaminoC₁₋₄-alkyl-;

each R⁴, independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅,—O—C₁₋₃-alkyl, —S—C₁₋₃-alkyl, —NH—C₁₋₃-alkyl, NO₂, NH₂, OH, CN, methyl,ethyl propyl or isopropyl;

R⁵ is C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷,NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸;

each R⁷, independently, is H, methyl, ethyl, propyl, isopropyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of thecyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionallysubstituted with 1-3 substituents of R⁹;

R⁸ is a ring selected from phenyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formula I include compounds, andpharmaceutically acceptable salts thereof, selected fromN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;

-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;-   N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;    and-   3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-5-fluoro-4-methylbenzamide.

In another embodiment, the invention provides compounds of Formula II,and pharmaceutically acceptable salts thereof, wherein

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

R² is H or halo;

R³ is CN, C(O)R⁷, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

R^(4a) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R^(4b) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R⁵ is COOR⁷, COOR⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸,NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸,NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the invention provides compounds of Formula III,and pharmaceutically acceptable salts thereof, wherein

B is O, S or N—CN;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with one or more substituentsof R⁹,

or R¹ is a 3-8 membered monocyclic or 6-12 membered bicyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein said ring system isoptionally substituted independently with one or more substituents ofR⁹;

R² is H or F;

R³ is CN, C(O)R⁷, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl andC₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with one or more substituents of R⁹;

R^(4a) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R^(4b) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In another embodiment, the compounds of Formulas II and III includecompounds wherein R⁸ is a ring selected from phenyl, naphthyl, pyridyl,pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹, inconjunction with any of the above or below embodiments.

In another embodiment, the invention provides compounds of FormulaIII-A, and pharmaceutically acceptable salts thereof, wherein

B is O or S;

R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl,each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyland C₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selectedfrom N, O and S and optionally substituted with 1-3 substituents of R⁹,

or R¹ is a ring selected from phenyl, pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl,pyrazlyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl,thiadiazolyl, said ring optionally substituted independently with 1-3substituents of R⁹;

R² is H or F;

R³ is CN, C(O)C₁₋₆-alkyl, C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆-alkynyl, eachof the C₁₋₆-alkyl, C₂₋₆-alkenyl and C₂₋₆-alkynyl optionally comprising1-4 heteroatoms selected from N, O and S and optionally substituted withone or more substituents of R⁹;

R^(4a) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

R^(4b) is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₆-alkyl;

each R⁷, independently, is H, C₁₋₆-alkyl or C₃₋₆-cycloalkyl, each of theC₁₋₆-alkyl, and C₃₋₆-cycloalkyl optionally substituted with one or moresubstituents of R⁹;

R⁸ is a ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,triazinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,wherein said ring is optionally substituted independently with 1-3substituents of R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl,butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine,diethylamine, propylamine, isopropylamine, dipropylamine,diisopropylamine, benzyl or phenyl.

In yet another embodiment, the compounds of Formulas I, II and IIIinclude each individual example, and each and every pharmaceuticallyacceptable salt form thereof, described hereinbelow.

DEFINITIONS

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, including the indicatedcomponent(s), but not excluding other elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀). Examplesof such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like.The term “alkylenyl” embraces bridging divalent alkyl radicals such asmethylenyl and ethylenyl.

The term “alkenyl”, when used alone or in combination, embraces linearor branched radicals having at least one carbon-carbon double bond in amoiety having between two and ten carbon atoms. Examples of alkenylradicals include, without limitation, ethenyl, propenyl, allyl,propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “loweralkenyl”, embrace radicals having “cis” and “trans” orientations, oralternatively, “E” and “Z” orientations, as appreciated by those ofordinary skill in the art.

The term “alkynyl”, when used alone or in combination, denotes linear orbranched radicals having at least one carbon-carbon triple bond andhaving two to ten carbon atoms. Examples of such radicals include,without limitation, ethynyl, propynyl (propargyl), butynyl, and thelike.

The term “alkoxy” or “alkoxyl”, when used alone or in combination,embraces linear or branched oxygen-containing radicals each having alkylportions of one or more carbon atoms. Examples of such radicals includemethoxy, ethoxy, propoxy, butoxy and tent-butoxy. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Examples of such radicalsinclude fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy,fluoroethoxy and fluoropropoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” ring system need not be aromatic, and the ring(s) fused to thearomatic ring may be partially or fully unsaturated and include one ormore heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. Unless otherwise specified, the “aryl”group may be subsitituted, such as with 1 to 5 substituents includinglower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and loweralkylamino, and the like. Phenyl substituted with —O—CH₂—O— or—O—CH₂—CH₂—O— forms an aryl benzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane andpartially saturated monocyclic groups such as cyclopentene, cyclohexeneor cyclohexadiene. The partially saturated groups are also encompassedin the term “cycloalkenyl” as defined below.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The terms “partially or fully saturated or unsaturated” and “saturatedor partially or fully unsaturated” with respect to each individual ring,refer to the ring either as fully aromatic (fully unsaturated),partially aromatic (or partially saturated) or fully saturated(containing no double or triple bonds therein). If not specified assuch, then it is contemplated that each ring (monocyclic) in a ringsystem (if bicyclic or tricyclic) may either be fully aromatic,partially aromatic or fully saturated, and optionally substituted withup to 5 substituents.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of heteroaryl radicals, include unsaturated 5- to 6-memberedheteromonocyclyl groups containing 1 to 4 nitrogen atoms, including forexample, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g.,4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heteroaryl” also embraces bicyclic radicals wherein 5- or6-membered heteroaryl radicals are fused/condensed with aryl radicals orunsaturated condensed heterocyclic groups containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of heterocyclic radicals includesaturated 3 to 6-membered heteromonocyclic groups containing 1 to 4nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of partially saturated and saturated heterocyclyl include,without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The terms “alkylthio” and “thioalkoxyl” embrace radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” is methylthio,(CH₃S—).

The term “Formula I” includes any sub formulas, such as Formulas II andIII.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I, II or III is intended to refer to a form of thecompound that is safe for administration. For example, a free base, asalt form, a solvate, a hydrate, a prodrug or derivative form of acompound of Formula I, II or of Formula III, which has been approved formammalian use, via oral ingestion or any other route of administration,by a governing body or regulatory agency, such as the Food and DrugAdministration (FDA) of the United States, is pharmaceuticallyacceptable.

Included in the compounds of Formulas I, II and III are thepharmaceutically acceptable salt forms of the free-base compounds. Theterm “pharmaceutically-acceptable salts” embraces salts, commonly usedto form alkali metal salts and to form addition salts of free acids orfree bases, which have been approved by a regulatory agency. Asappreciated by those of ordinary skill in the art, salts may be formedfrom ionic associations, charge-charge interactions, covalent bonding,complexation, coordination, etc. The nature of the salt is not critical,provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I and II may be prepared from an inorganic acid or from anorganic acid. Examples of such inorganic acids are hydrochloric,hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, sulfonic,sulfuric and phosphoric acid. Appropriate organic acids may be selectedfrom aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic,carboxylic and sulfonic classes of organic acids, examples of whichinclude, without limitation, formic, acetic, adipic, butyric, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I, II and III includemetallic salts, such as salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc, or salts made from organic basesincluding, without limitation, primary, secondary and tertiary amines,substituted amines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I, II or III.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained. Other examples include saltswith alkali metals or alkaline earth metals such as sodium, potassium,calcium or magnesium, or with organic bases.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66, 1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is broadly construed herein, and intended toencompass any salt of a compound of this invention, any ester of acompound of this invention, or any other compound, which uponadministration to a patient is capable of providing (directly orindirectly) a compound of this invention, or a metabolite or residuethereof, characterized by the ability to the ability to modulate akinase enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative, which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formula I. A “pharmaceutically-acceptable prodrug” as usedherein, denotes a prodrug, which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of FormulasI-III are readily appreciated by those of ordinary skill in the art.

The compound(s) of Formulas I, II or III may be used to treat a subjectby administering the compound(s) as a pharmaceutical composition. Tothis end, the compound(s) can be combined with one or more excipients,including carriers, diluents or adjuvants, to form a suitablecomposition, which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies.

The term “leaving groups” (also denoted as “LG”) generally refer togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I, II and III. The compounds of Formulas I, IIand III can be synthesized according to the procedures described in thefollowing Schemes 1-4, wherein the substituents are as defined forFormulas I, II and III, above, except where further noted. The syntheticmethods described below are merely exemplary, and the compounds of theinvention may also be synthesized by alternate routes as appreciated bypersons of ordinary skill in the art.

The following list of abbreviations used throughout the specificationrepresent the following and should assist in understanding theinvention:

ACN, MeCN acetonitrile BSA bovine serum albumin BOPbenzotriazol-1-yl-oxy hexafluorophosphate Br₂ bromine CDIcarbonyldiimidazole Cs₂CO₃ cesium carbonate CHCl₃ chloroform CH₂Cl₂, DCMdichloromethane, methylene chloride DCC dicyclohexylcarbodiimide DIC1,3-diisopropylcarbodiimide DIEA, (iPr)₂NEt diisopropylethylamine DMEdimethoxyethane DMF dimethylformamide DMAP 4-dimethylaminopyridine DMSOdimethylsulfoxide EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Et₂Odiethyl ether EtOAc ethyl acetate G, g, gm gram h, hr hour H₂ hydrogenH₂O water HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HBr hydrobromic acid HClhydrochloric acid HOBt 1-hydroxybenzotriazole hydrate HOAc acetic acidHPLC high pressure liquid chromatography IPA, IpOH isopropyl alcoholK₂CO₃ potassium carbonate LG leaving group MgSO₄ magnesium sulfate MSmass spectrum MeOH methanol N₂ nitrogen NaCNBH₃ sodium cyanoborohydrideNa₂CO₃ sodium carbonate NaHCO₃ sodium bicarbonate NaH sodium hydrideNaOCH₃ sodium methoxide NaOH sodium hydroxide Na₂SO₄ sodium sulfate NBSN-bromosuccinimide NH₄Cl ammonium chloride NH₄OH ammonium hydroxide NMPN-methylpyrrolidinone P(t-bu)₃ tri(tert-butyl)phosphine PBS phospatebuffered saline Pd/C palladium on carbon Pd(PPh₃)₄palladium(0)triphenylphosphine tetrakis Pd(dppf)Cl₂palladium(1,1-bisdiphenylphosphinoferrocene) II chloride Pd(OAc)₂palladium acetate PyBop benzotriazol-1-yl-oxy-tripyrrolidino-phosphoniumhexafluorophosphate RT, rt room temperature TBTUO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate TEA,Et₃N triethylamine TFA trifluoroacetic acid THF tetrahydrofuran UVultraviolet light

R1-substituted pyrazolo-pyrazinones 9, (wherein R1 in Formulas I-III isas defined herein or is an aromatic moiety, R4 is an alkyl moiety and R5is an amide as shown) may be made by the method generally described inScheme 1, also designated herein as Method A. As shown, anamino-cyano-pyrazolo 2 may be made from the reaction of an appropriatesubstituted hydrazine 1 (or it's HCl salt) with 2-(ethoxymethylene)malononitrile followed by hydrolysis and elimination of the cyano groupwith concentrated HCl under heat, to afford the amino-pyrazole 3.Pyrazole 3 can be nitrosolated to provide the nitroso-pyrazole compound4, by reaction with isoamylnitrite in the presence of suitable acidicconditions, such as those shown above. A literature reference for thisstep is further described in Hoehn, Hans.Pyrazolo[3,4-b]pyrazine-5-carboxylic acids, esters, nitriles, andamides. U.S. (1976), 9 pp. CODEN: U.S. Pat. No. 3,957,782. Ring closureof intermediate 5 can be afforded by reaction of nitroso-aminopyrazole 4with diethyl malonate under suitable basic conditions, such as withsodium ethoxide and heat. The ester group of intermediate 5 may beconverted to the corresponding bromo intermediate 6 via reaction with asuitable bromide source, such as NB S under suitable oxidizingconditions to provide the corresponding pyrazinone of compound 6. Theamide of compound 6 can be functionalized with a desireable R³ group,such as by an alkylation reaction with an alkyl iodide, as shown above,to afford intermediate 7-A, and as shown, 7-B as a by-product. Thebromine adduct 7-A can be subjected to suitable Suzuki Couplingconditions, such as those shown in scheme 1, with a desired boronicester intermediate 8 to afford the desired substitutedpyrazolo-pyrazinones 9.

The boronic ester intermediates 8 (the phenyl or pyridine ring ofcompound 8 is also referred to herein as ring “B”) may be prepared bymethods described in the following references: (1) PCT Int. Patent Appl.No. WO 2005073189, titled “Preparation of fused heteroaryl derivativesas p38 kinase inhibitors” or (2) PCT Int. Patent Appl. No. WO2006094187, titled “Preparation of phthalazine, aza- anddiaza-phthalazine compounds as protein kinase, especially p38 kinase,inhibitors for treating inflammation and related conditions”, bothpublications of which are hereby incorporated herein by reference intheir entirety.

The Suzuki method is a reaction using a borane reagent, such as adioxaborolane intermediate 8 (also described in scheme 3 below as aborane B-A intermediate 8), and a suitable halogen coupling partner,such as the Br-pyrazolo-pyrazinone 7-A (Br is a suitable halogencoupling partner). As appreciated to one of ordinary skill in the art,Suzuki reactions also utilize a palladium catalyst. Suitable palladiumcatalysts include Pd(PPh₃)₄, Pd(OAc)₂ or Pd(dppf)Cl₂. Where the couplingpartner is a halide, the halide may be an iodide, a bromide or even achloride (chloro-pyridyl or chloro-picolinyl B rings undergo Suzukireactions in the presence of Pd(OAc)₂). Other coupling partners are alsosuitable. For example, Suzuki couplings are known to occur with asulfonate, such as trifluoromethanesulfonate, as the leaving group.

The Suzuki reaction conditions may vary. For example, Suzuki reactionsare generally run in the presence of a suitable base such as a carbonatebase, bicarbonate or an acetate base, in a suitable solvent such asdioxanes, acetonitrile, DMF or an aqueous-organic solvent combination ora biphasic system of solvents. Furthermore, the reaction may requireheat depending upon the particular pyrazolo-pyrazinone 7-A and/orboronic acid or ester 8, as appreciated by those skilled in the art. Inaddition, where the B ring is an aromatic moiety, such as phenyl, thereaction may be complete in a short period of time with heat.

Other methods of installing the boronate on a desired aromatic ring areknown. For example metal coupling chemistry, such Stille, Kumada,Negishi coupling methods, and the like, may be employed to thepyrazolo-pyrazinone cores 7-A to prepare desired cyclicB-ring-substituted intermdiates.

Alternatively, substituted pyrazolo-pyridinones 9 may be made by themethod generally described in Scheme 2, also designated herein as MethodB. In method B, compound 7-C can be subjected to suitable SuzukiCoupling conditions, such as those shown in scheme 2 above, with adesired boronic acid, acid intermediate 8-A to afford the desiredsubstituted acid-pyrazolo-pyridinone 10. Acid 10 can be furtherfunctionalized, such converted to the corresponding amide usingconventional methods, such as by activating the acid via an acidchloride (shown above), followed by reaction with a desired primary orsecondary amine, or other suitable nucleophile (not shown) to afford thefinal desired compound 9.

Substituted pyrazolo-pyridinethiones 9-A may be made by the methodgenerally described in Scheme 3. As shown, the ketone of thebromo-pyrazolo-pyridinone intermediate 7-A can be converted to thecorresponding thio-ketone 7-D using conventional methods, such as withLawessen's Reagent under suitable conditions. Thio-ketone 7-D can bereacted with a boronate 8 (as shown in Method A, Scheme 1) undersuitable Suzuki or Suzuki-like coupling conditions to afford the coupledadduct 9-A.

Various other linker R⁵ groups are within the scope of the presentinvention. Such other linkers may be made using the general methodsdescribed in scheme 4 below. As illustrated in scheme 4, desirable R⁷and R⁸ groups are shown as a ring designated as ring A. However, thepresent invention is not so limited, and it is intended that what isdepicted as “ring A” in scheme 4 should be read to also include noncyclic moieties attached to linker R⁵, as described in Formulas I, IIand III herein.

The B ring, as illustrated in scheme 4, is substituted by a linker groupR⁵. The R⁵ linker group, including an amino, a carboxyl, a sulfonyl, anamido or a urea linker, as defined herein in Formulas I, II and III,connect various substitutions, including R⁷ non-cyclic moieties or R⁷and R⁸ cyclic rings (generally designated and referred to in Scheme 4,and throughout the specification, as the “A” group or “A” ring) to the“B” ring. This linker may be attached by various coupling methods asdescribed in Scheme 4. Each of the nine sub-schemes, numbered 1-9 aboveand described below, utilize the following meanings for (R)_(n), X, Nu⁻,E⁻ and m: (R)_(n) refers to n number of R⁷ and R⁸ substitutions whereinn is an integer from 0-5; X refers generally to a “leaving group” (alsorefered to herein as “LG”) such as a halide (bromine, chlorine, iodineor fluorine), alkylsulfonate and other known groups (also seedefinitions herein); Nu⁻ refers generally to a nucleophilic species suchas a primary or secondary amine, an oxygen, a sulfur or a anionic carbonspecies—examples of nucleophiles include, without limitation, amines,hydroxides, alkoxides and the like; E⁺ refers generally to anelectrophilic species, such as the carbon atom of a carbonyl, which issusceptible to nucleophilic attack or readily eliminates—examples ofsuitable electrophilic carbonyl species include, without limitation,acid halides, mixed anhydrides, aldehydes, carbamoyl-chlorides, sulfonylchlorides, acids activated with activating reagents such as TBTU, HBTU,HATU, HOBT, BOP, PyBOP and carbodiimides (DCC, EDC, CDI and the like),and other electrophilic species including halides, isocyanates,daizonium ions and the like; and m is either 0 or 1.

The coupling of ring B to A, as shown as products in sub-schemes 1-9,can be brought about using various conventional methods to link ring Band A together. For example, an amide or a sulfonamide linkage, as shownin sub-schemes 2 and 4, and 7 and 9 where the Nu− is an amine,respectively, can be made utilizing an amine on either the B or A groupsand an acid chloride or sulfonyl chloride on the other of either the Bor A groups. The reaction proceeds generally in the presence of asuitable solvent and/or base. Suitable solvents include, withoutlimitation, generally non-nucleophilic, anhydrous solvents such astoluene, CH₂Cl₂, THF, DMF, DMSO, N,N-dimethylacetamide and the like,including solvent combinations thereof The solvent may range inpolarity, as appreciated by those skilled in the art. Suitable basesinclude, for example, tertiary amine bases such as DIEA, TEA, carbonatebases such as Na₂CO₃, K₂CO₃, Cs₂CO₃, hydrides such as NaH, KH,borohydrides, cyanoborohydrides and the like, alkoxides such as NaOCH₃,and the like. The base itself may also serve as a solvent. The reactionmay optionally be run neat, i.e., without any base and/or solvent. Thesecoupling reactions are generally fast and conversion occurs typically inambient conditions. However, depending upon the particular substrate,such reactions may require heat, as appreciated by those skilled in theart.

Similarly, carbamates as illustrated in sub-schemes 5 and 1 where Nu− isan amine, anhydrides as illustrated in sub-scheme 1 where Nu− is anoxygen, reverse amides as generally illustrated in sub-scheme 8 whereNu− is an amine and E+ is an acid chloride, ureas as illustrated insub-scheme 3, thioamides and thioureas where the respective carbonyloxygen is a sulfur, thiocarbamates where the respective carbonyl oxygenand/or carbamate oxygen is a sulfur, and the like. While the abovemethods are so described, they are not exhaustive, and other methods forlinking groups A and B together may be utilized as appreciated by thoseskilled in the art.

Although sub-schemes 1-9 are illustrated as having the nucleophilic andelectrophilic coupling groups, such as the amino group and acid chloridegroups illustrated in sub-scheme 2, directly attached to the substrate,either the A group or B ring, in question, the invention is not solimited. It is contemplated herein that these nucleophilic and/orelectrophilic coupling groups may be tethered from their respectivering. For example, the amine group on the B ring, and/or the acid halidegroup on the A group or ring, as illustrated in sub-scheme 2, may beremoved from direct attachment to the ring by a one or more atom spacer,such as by a methylene, ethylene spacer or the like. As appreciated bythose skilled in the art, such spacer may or may not affect the couplingreactions described above, and accordingly, such reaction conditions mayneed to be modified to effect the desired transformation.

The coupling methods described in sub-schemes 1-9 of scheme 6 are alsoapplicable for coupling desired A groups or rings to desiredpyrazolo-pyridinone-B ring intermediates, such as to substituted B ringcarboxylic acids (Scheme 2) to synthesize desired compounds of FormulasI, II and III. For example, a desirably substitutedpyrazolo-pyridinone-benzoic acid maybe reacted with a desirablysubstituted primary or secondary amine, such as an NHR⁷R⁷ or NHR⁷R⁸group in the presence of a suitable solvent and a known couplingreagent, such as TBTU, HATU, CDI or others, to prepare the desired A-Bamide bond, and the final compound of Formulas I, II or III.

Note that the B-A moiety is connected through a linker “L”. “L” may beany linker generally defined by the R⁵ groups in Formulas I, II and III,and particularly, it includes, without limitation, an amide, a urea, athiourea, a thioamide, a carbamate, an anhydride, a sulfonamide and thelike.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I, II and III) and methods of making compounds ofthe invention are set forth. It should be appreciated that the abovegeneral methods and specific examples below are merely for illustrativepurposes only and are not to be construed as limiting the scope of thisinvention in any manner. The following analytical methods were used topurify and/or characterize the compounds, and intermediates, describedin the examples below.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a AgilentModel 1100 system with an Agilent Technologies Zorbax SB-C₈(5μ) reversephase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flowrate of about 1.50 mL/min. The mobile phase used solvent A (H₂O/0.1%TFA) and solvent B (ACN/0.1% TFA) with a 11 min gradient from 5% to 100%ACN. The gradient was followed by a 2 min. return to 5% ACN and about a2.5 min. re-equilibration (flush).

LC-MS Method:

Samples were run on an Agilent model-1100 LC-MSD system with anPhenomenex Synergi MAX-RP (4.0μ) reverse phase column (2×50 mm) at 40°C. The flow rate was constant and ranged from about 0.75 mL/min to about1.0 mL/min.

The mobile phase used a mixture of solvent A (H₂O/0.1% TFA) and solventB (ACN/0.1% TFA) with a 5 min time period for a gradient from 10% to100% solvent B. The gradient was followed by a 0.5 min period to returnto 10% solvent B and a 1.5 min 10% solvent B re-equilibration (flush) ofthe column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phaseHPLC using a Gilson workstation utilizing one of the following twocolumns and methods: (A) Using a 50×100 mm column (Waters, Externa, C18,5 microns) at 50 mL/min. The mobile phase used was a mixture of solventA (H₂O/10 mM ammonium carbonate at pH about 10, adjusted with conc.NH₄OH) and solvent B (85:15 ACN/water, 10 mM ammonium carbonate at pH ofabout 10 adjusted with conc. NH₄OH). Each purification run utilized a 10minute gradient from 40% to 100% solvent B followed by a 5 minute flowof 100% solvent B. The gradient was followed by a 2 min return to 40%solvent B. (B) Using a 20×50 mm column at 20 mL/min. The mobile phaseused was a mixture of solvent A (H₂O/0.1% TFA) and solvent B (ACN/0.1%TFA) with a 10 min gradient from 5% to 100% solvent B. The gradient isfollowed by a 2 min return to 5% ACN.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Varianseries Mercury 300 MHz instrument or a Bruker series 400 MHz instrument.Where so characterized, all observed protons are reported asparts-per-million (ppm) downfield from tetramethylsilane (TMS) or otherinternal reference in the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method. Compounds havingan isotopic atom, such as bromine and the like, are reported accordingto the detected isotopic pattern, as appreciated by those skilled in theart.

EXAMPLE 1 Via Method A

Synthesis ofN-Cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamideStep 1: 1-(2,6-Difluorophenyl)-1H-pyrazol-5-amine

(A): To a solution of 1-(2,6-difluorophenyl)hydrazine hydrochloride(12.38 g, 68.56 mmol) in anhydrous ethanol (70 mL) was added2-(ethoxymethylene)malononitrile (8.791 g, 71.98 mmol) followed bytriethylamine (10.01 mL, 71.98 mmol), and the contents stirred at RT for10 min and then heated to reflux for 1.5 h. The contents were cooled toRT and solvents removed under reduced pressure. The resulting brownsolid was stirred with 50 mL of water and 250 mL of EtOAc. The EtOAclayer was separated, washed with 50 mL of brine, dried and concentrated.The concentrated solid was stirred in 50 mL of hexanes for 5 min,filtered through a flitted funnel, and dried in a vacuum oven at 45° C.for 2 h to afford5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile as a brownsolid. This material was used without further purification. MS (ES+):221.1 (M+H)⁺.(B): A mixture of5-amino-1-(2,6-difluorophenyl)-1H-pyrazole-4-carbonitrile (14 g, 64mmol) in 50 mL of concentrated HCl was refluxed for 10 h. The reactionmixture was concentrated to half of its volume, cooled with an ice bath,pH adjusted to about 10 with 10 N NaOH, and extracted with 3×100 mL ofEtOAc. The combined organic layers were washed with brine, dried andconcentrated to afford 1-(2,6-difluorophenyl)-1H-pyrazol-5-amine as abrown amorphous solid. This material was used without furtherpurification. MS (ES+): 196.1 (M+H)⁺.

Step 2: 1-(2,6-Difluorophenyl)-4-nitroso-1H-pyrazol-5-amine

Additional description for this step may be found in: Hoehn, Hans.Pyrazolo[3,4-b]pyrazine-5-carboxylic acids, esters, nitriles, andamides. U.S. (1976), 9 pp. CODEN: U.S. Pat. No. 3,957,782

To a solution of (2,6-difluorophenyl)-1H-pyrazol-5-amine (2.60 g, 13.3mmol) in 8 mL of EtOAc and 4 mL of EtOH was added 8 mL of HCl in2-propanol (5-6 N). The heterogeneous mixture was cooled with anice-NaCl bath, and isopentyl nitrite (1.83 mL, 13.6 mmol) was added dropwise (within 10 min) to prevent the temperature from exceeding 10° C.After stirring for 15 min, the reaction mixture became homogeneous.Stirring was continued for a total of 40 min. The brown homogeneoussolution was diluted with 150 mL of EtOAc, and neutralized with ammoniumhydroxide. The EtOAc layer was separated and washed with brine to afforda rusty crystalline solid which was triturated with 15 mL Hexanes. Therusty solid was collected and dried in a vacuum oven at 45° C. for 2 hto afford 1-(2,6-difluorophenyl)-4-nitroso-1H-pyrazol-5-amine This crudematerial was used without further purification. MS (ES+): 225.1 (M+H)⁺.

Step 3: Ethyl1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate

Additional description for this step may be found in: Hoehn, Hans.Pyrazolo[3,4-b]pyrazine-5-carboxylic acids, esters, nitriles, andamides. U.S. (1976), 9 pp. CODEN: U.S. Pat. No. 3,957,782

To a solution of diethyl malonate (4.1 mL, 27 mmol) in 10.0 mL of EtOHat RT was added sodium ethoxide (10 mL of the 21% wt. in denatured ethylalcohol, 28 mmol) followed by 5 min later, the addition of1-(2,6-difluorophenyl)-4-nitroso-1H-pyrazol-5-amine (5.13 g, 23 mmol) asa solid. The resulting mixture was refluxed for 4 h. The volatiles wereremoved under reduced pressure and the remaining residue was partitionedbetween 50 mL of EtOAc and 30 mL of saturated NH₄Cl solution. Theprecipitated rusty solid was filtered, rinsed with 2×5 mL of waterfollowed by 2×10 mL of EtOAc. The rusty solid was dried in vacuum ovenat 45° C. for 4 h to provide 4.3 g of ethyl1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate.The filtrate was transferred to a separatory funnel. The EtOAc layer wasseparated and washed with brine, dried and concentrated. Purification ofthe dark brown residue on a silical gel column (25-65% EtOAc in Hexanes)afforded 1.1 g of ethyl1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylateas a brown solid. MS (ES+): 321.1 (M+H)⁺. MS (ES+): 343.0 (M+Na)⁺.

Step 4:5-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one

To a mixture of ethyl1-(2,6-difluorophenyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyrazine-5-carboxylate(1.27 g, 3.70 mmol) in 2.5 mL of water and 2.5 mL of CH₃CN at RT wasadded lithium hydroxide (209 mg, 8.72 mmol), and the resulting mixturewas warmed to 60° C. for 0.5 h. The reaction mixture was cooled with anice bath, and NBS (1059 mg, 5.95 mmol) was added in small portions. Thereaction mixture was stirred at RT for 0.5 h, then partitioned between asaturated solution of NaHCO₃ and EtOAc. The EtOAc layer was washed withbrine, dried over MgSO₄, filtered and concentrated to afford5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (1210mg, 93.3% yield) a a brown amorphous solid. This crude material was usedwithout further purification. MS (ES+): 327.0/329.0 (M+H)⁺.

Step 5:5-Bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one

A mixture of5-bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (981mg, 3.0 mmol) in 10 mL of DME and 1 mL of DMF at RT was treated withlithium hydride (119 mg, 15 mmol) in small portions. Iodomethane (0.62mL, 9.9 mmol) was added 30 min later. The mixture was stirred at RT for18 h, and poured into an ice cold sat. NH₄Cl solution, then extractedtwice with EtOAc. The combined EtOAc layes were washed with brine, driedand concentrated. Purification of the crude material on a silical gelcolumn (25-85% EtOAc in Hexanes) provided: (1)5-bromo-1-(2,6-difluorophenyl)-6-methoxy-1H-pyrazolo[3,4-b]pyrazine (65mg, 6.4% yield) as an off white crystalline solid. MS (ES+): 341.0/343.0(M+H)⁺; and (2)5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one(616 mg, 60% yield) as an off white amorphous solid. MS (ES+):341.0/343.0 (M+H)⁺.

Step 6:N-Cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide

A mixture ofN-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(520 mg, 1.63 mmol),5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one(505 mg, 1.48 mmol) in 3.5 mL of dioxane and 1.5 mL of 2 N Na2CO3 washeated in a microwave at 125° C. for 25 min. It was diluted with EtOAcand washed with 1 N NaOH. The EtOAc layer was separated, dried andconcentrated. Purification of the crude material on an ISCO 40 g column(with 30-75% EtOAc in Hexanes) providedN-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide as an off white amorphous solid. MS (ES+): 454.1 (M+H)⁺.

EXAMPLE 2 Via Method B

Synthesis of3-(1-(2,4-Difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamideStep 1: 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine

A 250 mL RBF containing a solution of 1-(2,4-difluorophenyl)hydrazinehydrochloride (10.33 g, 57 mmol), Et₃N (8.0 mL, 57 mmol), EDTA disodiumsalt dihydrate (50 mg, 0.13 mmol) in 100 mL of MeOH was fitted with areflux condenser, and heated to 70° C. To the refluxing solution wasadded 2-chloroacrylonitrile (5.0 mL, 57 mmol) slowly. The solution washeated at reflux for an additional 7.5 h. It was cooled to RT thenconcentrate sulfuric acid (5.2 mL, 97 mmol) was added slowly and thereaction mixture again heated to reflux for 18 h. The reaction mixturewas cooled to 0° C. and treated with Na₂CO₃ monohydrate (21.00 g) andstirred at RT for 8 h. The reaction mixture was concentrated on therotovap to remove the MeOH. The resulting rust colored solid was thentreated with 100 mL of water and extracted with EtOAc (2×100 mL). Thecombined EtOAc layers were washed with brine, dried and concentrated.Purification of the crude material on an ISCO 120 g column (20-80% EtOAcin hexanes) afforded 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine as anorange-brown viscous oil. MS (ES+): 196.1 (M+H)⁺. A further generaldescription of this procedure can be found in U.S. Pat. No. 4,803,215.

Step 2: 1-(2,4-Difluorophenyl)-N-ethyl-1H-pyrazol-5-amine

A solution of 1-(2,4-difluorophenyl)-1H-pyrazol-5-amine (5.00 g, 26mmol), in 80 mL of 1,2-DCE was added DMAP (0.94 g, 7.7 mmol), Ac₂O (12mL, 128 mmol) and Et₃N (18 mL, 128 mmol). The dark brown reactionmixture was heated at 80° C. in an oil bath for 18 h. After cooling toRT, it was diluted with 20 mL of DCM and washed with saturated aqueoussolution of sodium bicarbonate, and brine. The resulting organicsolution was then dried over magnesium sulfate and concentrated underreduced pressure to give viscous brown oil which contains thebis-acylated product along with residual amount of Ac₂O and AcOH. Theviscous brown oil was dissolved in 50 mL of EtOH and treated with KOH(5.0 g 129 mmol). After the reaction mixture was stirred at RT for 4 h,it was acidified with 2 N HCl to pH 4. The volatile portion was removedon the rotovap. The residue was diluted with 150 mL of EtOAc, washedwith saturated aqueous solution of sodium bicarbonate, and brine. Theresulting organic solution was then dried over magnesium sulfate andconcentrated under reduced pressure. Purification of the crude materialon an ISCO 80 g column (60-100% EtOAc in hexanes) affordedN-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide as an off-whitesolid. MS (ES+): 238.1 (M+H)⁺.

At 0° C., a solution ofN-(1-(2,4-difluorophenyl)-1H-pyrazol-5-yl)acetamide (2.58 g, 10.88 mmol)in 35 mL of THF was treated with lithium aluminum hydride (22 mL of the1.0 M solution in THF, 22 mmol). The reaction mixture was stirred at 0°C. for 90 min then quenched with Rochelle's salt. It was extracted withEtOAc (3×100 mL) followed by DCM (2×50 mL). The combined organicsolution was dried over MgSO₄, filtered and concentrated. Purificationof the crude material on an ISCO 80 g column (30-80% EtOAc in hexanes)afforded 1-(2,4-difluorophenyl)-N-ethyl-1H-pyrazol-5-amine (1.21 g, 50%yield) as a light yellow viscous oil. MS (ES+): 224.1 (M+H)⁺.

Step 3: 1-(2,4-Difluorophenyl)-N-ethyl-4-nitroso-1H-pyrazol-5-amine

A solution of 1-(2,4-difluorophenyl)-N-ethyl-1H-pyrazol-5-amine (1.15 g,5.16 mmol) in 4.0 mL of EtOAc, 2.0 mL of EtOH and 4.0 mL of 5-6 N HCl in2-propanol was cooled in an ice/brine bath and treated with isoamylnitrite (0.70 mL, 5.28 mmol) drop wise. After stirring at thistemperature for 15 min, the reaction was quenched by the addition of28-30% NH₄OH solution and EtOAc, forming a deep blue solution. The EtOAclayer was separated, washed with brine, dried and concentrated to affordthe title compound as a brown crystalline solid. MS (ES+): 253.1 (M+H)⁺.

Step 4: 1-(2,4-Difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine

A solution of1-(2,4-difluorophenyl)-N-ethyl-4-nitroso-1H-pyrazol-5-amine (1.21 g, 5mmol) in 20 mL of MeOH was hydrogenated for 3 h with hydrogen gas in aballoon in the presence of palladium (200 mg of the 10% wt. on activatedcarbon). The reaction mixture was filtered through a pad of celitewashing with MeOH. The solvent was removed on the rotovap affording1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine as a brightorange viscous oil. This material was used without purification. MS(ES+): 224.1 (M+H)⁺.

Step 5:1-(2,4-Difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione

A mixture of diethyl oxalate (5.68 mL, 4.20 mmol) and1-(2,4-difluorophenyl)-N5-ethyl-1H-pyrazole-4,5-diamine (1.00 g, 4.20mmol) were heated in an oil bath at 150° C. for 18 h. The reactionmixture was cooled to RT and treated with EtOAc (5 mL) and hexanes (15mL). The precipitated tan solid was filtered and rinsed with 5 mL ofether to afford1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione.MS (ES+): 293.1 (M+H)⁺.

Step 6:5-Chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one

A mixture of1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[3,4-b]pyrazine-5,6(4H,7H)-dione(330 mg, 1.13 mmol) in 5 mL of toluene was treated with POCl₃ (0.16 mL,1.70 mmol) followed by N,N-diisopropylethylamine (0.16 mL, 0.9 mmol).The reaction mixture was heated in an oil bath at 110° C. for 2.5 h. Thevolatiles were removed on the rotovap and the residue was dissolved inice cold DCM (20 mL) and washed with NaHCO₃ saturated solution, driedover MgSO₄, filtered and concentrated affording5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-oneas a brown amorphous solid. The material was used without furtherpurification. MS (ES+): 311.0 (M+H)⁺.

Step 7:3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoicacid

A mixture of tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 μmol),3-borono-5-fluoro-4-methylbenzoic acid (175 mg, 0.88 mmol) and5-chloro-1-(2,4-difluorophenyl)-7-ethyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one(250 mg, 0.80 mmol) in 4.0 mL dioxane and 2.0 mL of 1 N sodium carbonatewas heated in a microwave at 130° C. for 30 min. The reaction mixturewas treated with EtOAc (15 mL) and extracted with 1N NaOH (3×10 mL). Theaqueous extracts were treated with 5 N HCl to pH 2 and extracted withDCM (3×15 mL). The combined DCM layers were dried over MgSO₄, filteredand concentrated affording3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoicacid as a light orange-brown viscous oil. This material was used withoutpurification. MS (ES+): 429.1 (M+H)⁺.

Step 8:3-(1-(2,4-Difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamide

A solution of3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylbenzoicacid (360 mg, 0.84 mmol) in 5.0 mL of DCM was treated with oxalylchloride (0.84 mL of 2.0 M in DCM solution, 1.68 mmol) followed by twodrops of DMF while cooling in an ice bath at 0° C. It was stirred atthis temperature for 15 min then allowed to stir at RT for 45 min. Thereaction mixture was then concentrated under reduce pressure to removethe excess oxalyl chloride. The residue was dissolved in 5.0 mL of DCM,treated with 3-aminoisoxazole (212 mg, 2.52 mmol) followed by Et₃N (0.18mL, 1.26 mmol) and stirred for 18 h. The reaction mixture was treatedwith 15 mL saturated NaHCO₃ and extracted with DCM (2×15 mL). Thecombined DCM layers were dried over MgSO₄. Purification on the ISCO (12g column, 20-70% EtOAc in hexanes) afforded3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-N-(isoxazol-3-yl)-4-methylbenzamideas a light yellow amorphous solid. MS (ES+): 495.1 (M+H)⁺.

The detailed descriptions of Examples 1 and 2 fall within the scope, andserve to exemplify the above-described General Synthetic Procedureswhich form part of the invention. These detailed descriptions are notintended as a restriction on the scope of the invention. The followingExamples in Table 1 will further assist in understanding andappreciating the invention. The compounds of examples 3-10 were made inaccordance with exemplary methods A-B which correspond to above Examples1-2, respectively, and named according to the ACD naming convention, asassociated with ISIS software. The mass spectral data is recorded M+H+,which is the positive ion as measured by an electrospray ionizationmethod. The biological assay data is provided for those exemplarycompounds in Table 1 which were tested in, and data calculated from, thehuman whole blood and cellular assays. Not every compound example wasrun in the assays at the time of filing of this application, andaccordingly no data is provided in the Table.

TABLE 1 WB TNF/IL8 p38a Ex. MS IC50 IC50 No Name (M + H+) Method (nM)(nM) 3 N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 436.1 A 7.3 3.3methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide 43-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 396.1 A 41 8.56,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)- 4-methylbenzamide 1N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 454.1 A 10.7 1.8methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide 5N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 450.1 A 5.8 1.4ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide 63-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 481.1 B 3.2 1.26,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide 7N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 454.1 A 25 34methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide 83-(1-(2,4-difluorophenyl)-7-methyl-6-oxo- 481.1 A 13 4.66,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide 9N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7- 468.1 A 8.4 5ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide 103-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 463.1 B 3.7 106,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-4-methylbenzamide 23-(1-(2,6-difluorophenyl)-7-methyl-6-oxo- 495.1 B 6.1 2.56,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-5-fluoro-4-methylbenzamide 11N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7- 468.1 A 3 2.3ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide 123-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7- 428 A 23 22dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5- fluoro-4-methylbenzamide 133-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7- 477 B 1.2 0.7dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-4-methylbenzamide

The following compounds in Table 2 are additional representativeexamples of Formula I as provided by the present invention.

TABLE 2

Ex. No. R¹ R³ R^(4a) R^(4b) R⁷ or R⁸ 14 3,5-difluoro-Ph —CH₂CH₃ CH₃ Foxazolyl 15 2,4-difluoro-Ph —CH₃ CH₃ H methyl or cyclopropyl 162,6-difluoro-Ph —CH₂CH₃ CH₃ F methyl or cyclopropyl 17 2,4-difluoro-Ph—CH₃ Cl Cl methyl or cyclopropyl 18 2,6-difluoro-Ph —CH₃ F CH₃ methyl orcyclopropyl 19 m-CH₃-phenyl- —CH₂CH₃ Cl F methyl or cyclopropyl 20m-Cl-phenyl- —CH₂CH₃ OCH₃ F methyl or cyclopropyl 213,5-difluoro-Pyridine acetyl CH₃ F imidazolyl 22 2,4-difluoro-Ph propylCH₃ H thiazolyl 23 2,6-difluoro-Ph —CH₂CH₃ Cl F isothiazolyl 242,4-difluoro-Ph —CH₃ F Cl isoxazolyl 25 2,6-difluoro-Ph propyl Cl CH₃thiadiazolyl 26 m-CH₃-phenyl- butyl OCH₃ F N-methyl- pyrazolyl 27m-Cl-phenyl- acetyl CH₃ F triazolyl 28 3,5-difluoro-Ph —CH₂OH CH₃ Himidazolyl 29 2,4-difluoro-Ph —CH₂CH₃ Cl H thiazolyl 30 2,6-difluoro-Ph—CH₃ F F isothiazolyl 31 2,4-difluoro-Ph propyl Cl Cl isoxazolyl 322,6-difluoro-Ph —CH₂CH₃ OCH₃ CH₃ thiadiazolyl 33 m-CH₃-phenyl- —CH₃ CH₃F pyrazolyl 34 m-Cl-phenyl- acetyl CH₃ F triazolyl 35 3,5-difluoro-Ph—CH₂CH₃ Cl F imidazolyl 36 2,4-difluoro-Ph —CH₃ F H thiazolyl 373,5-difluoro-Ph —CH2CH3 CH3 F isoxazolyl 38 2-morpholine —CH3 CH3 Hpyrazolyl 39 3-piperazine —CH2CH3 CH3 F imidazolyl 40 2-piperidine —CH3Cl Cl triazolyl 41 phenyl —CH3 F CH3 tetrazolyl 42 m-CH3-phenyl- —CH2CH3Cl F thioazolyl 43 2-Cl-phenyl —CH2CH3 OCH3 F isothiazolyl 442-CH3-phenyl acetyl CH3 F phenyl 45 4-CH3-phenyl propyl CH3 Hcyclopropyl 46 4-Cl-phenyl —CH2CH3 Cl F ethyl 47 3-Cl-phenyl —CH3 F Clpropyl 48 3-CH3-phenyl propyl Cl CH3 butyl 49 2-thiophene butyl OCH3 Fisopropryl 50 3-thiophene acetyl CH3 F isobutyl 51 2-pyridine —CH2OH CH3H cyclopentyl 52 2-morpholinyl —CH2CH3 Cl H ethyl 53 4-piperazinyl —CH3F F ethyl 54 2-piperidinyl propyl Cl Cl ethyl 55 3,5-difluoro-Ph —CH2CH3OCH3 CH3 ethyl 56 3-Cl-phenyl —CH3 CH3 F ethyl 57 3-CH3-phenyl acetylCH3 F ethyl 58 2-thiophene —CH2CH3 Cl F ethyl 59 phenyl —CH3 F Hisoxazolyl 60 3-amido-2- pyrrolidinyl —CH2CH3 CH3 F pyrazolyl 613-amido-3- piperidinyl —CH3 CH3 H imidazolyl 62 4-amido-1- piperidinyl—CH2CH3 CH3 F triazolyl 63 4N—CH3-2- piperizinyl —CH3 Cl Cl tetrazolyl64 2-Cl-phenyl —CH3 F CH3 thioazolyl 65 2-CH3-phenyl —CH2CH3 Cl Fisothiazolyl 66 4-CH3-phenyl —CH2CH3 OCH3 F phenyl 67 4-Cl-phenyl acetylCH3 F cyclopropyl 68 3-Cl-phenyl propyl CH3 H ethyl 69 3-CH3-phenyl—CH2CH3 Cl F propyl 70 2-thiophene —CH3 F Cl ethyl 71 3-thiophene propylCl CH3 ethyl 72 2-pyridine butyl OCH3 F ethyl 73 2-morpholinyl acetylCH3 F cyclopropyl 74 3-piperazinyl —CH2OH CH3 H propyl 75 4-piperidinyl—CH2CH3 Cl H cyclopropyl 76 cyclohexyl-N— —CH3 F F cyclopropyl 77morpholine- (CH2)2—N— propyl Cl Cl propyl 78 (CH3)2N—(CH2)2— —CH2CH3OCH3 CH3 propyl 79 (C2H5)2N—(CH2)2— —CH3 CH3 F cyclopropyl 803-OH-1-pyrrolidinyl acetyl CH3 F propyl 81 —CH2CH3— —CH2CH3 Cl F propyl82 —(CH2)2CH3— —CH3 F H isoxazolyl 83 —CH3— —CH2CH3 CH3 F pyrazolyl 844N—CH3-2- piperizinyl —CH3 CH3 H imidazolyl 85 2-Cl-phenyl —CH2CH3 CH3 Ftriazolyl 86 2-CH3-phenyl —CH3 Cl Cl tetrazolyl 87 4-CH3-phenyl —CH3 FCH3 thioazolyl 88 4-Cl-phenyl —CH2CH3 Cl F isothiazolyl 89 3-Cl-phenyl—CH₂CH₃ OCH₃ F phenyl 90 3-CH₃-phenyl acetyl CH₃ F cyclopropyl 912-thiophene propyl CH₃ H ethyl 92 3-thiophene —CH₂CH₃ Cl F propyl 932-pyridine —CH₃ F Cl isoxazolyl 94 4-F-phenyl propyl Cl CH₃ pyrazolyl

While the examples and schemes described above provide processes forsynthesizing compounds, and intermediates thereof, of Formulas I, II andIII, it should be appreciated that other methods may be utilized toprepare such compounds. Methods involving the use of protecting groupsmay be used. Particularly, if one or more functional groups, for examplecarboxy, hydroxy, amino, or mercapto groups, are or need to be protectedin preparing the compounds of the invention, because they are notintended to take part in a specific reaction or chemical transformation,various known conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

The protection of functional groups by protecting groups, the protectinggroups themselves, and their removal reactions (commonly referred to as“deprotection”) are described, for example, in standard reference works,such as J. F. W. McOmie, Protective Groups in Organic Chemistry, PlenumPress, London and New York (1973), in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York (1981), in The Peptides, Volume 3, E.Gross and J. Meienhofer editors, Academic Press, London and New York(1981), in Methoden der Organischen Chemie (Methods of OrganicChemistry), Houben Weyl, 4^(th) edition, Volume 15/1, Georg ThiemeVerlag, Stuttgart (1974), in H.-D. Jakubke and H. Jescheit, Aminosauren,Peptide, Proteine (Amino Acids, Peptides, Proteins), Verlag Chemie,Weinheim, Deerfield Beach, and Basel (1982), and in Jochen Lehmann,Chemie der Kohlenhydrate: Monosaccharide and Derivate (Chemistry ofCarbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag,Stuttgart (1974).

Salts of a compound of the invention having a salt-forming group may beprepared in a conventional manner or manner known to persons skilled inthe art. For example, acid addition salts of compounds of the inventionmay be obtained by treatment with an acid or with a suitable anionexchange reagent. A salt with two acid molecules (for example adihalogenide) may also be converted into a salt with one acid moleculeper compound (for example a monohalogenide); this may be done by heatingto a melt, or for example by heating as a solid under a high vacuum atelevated temperature, for example from 50° C. to 170° C., one moleculeof the acid being expelled per molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplarysalt forms and their preparation are described herein in the Definitionsection of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., ethyl acetate; ethers includingaliphatic ethers, e.g., Et₂O and ethylene glycol dimethylether or cyclicethers, e.g., THF; liquid aromatic hydrocarbons, including benzene,toluene and xylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n-and t-butanol; nitriles including CH₃CN; halogenated hydrocarbons,including CH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides,including DMSO; bases, including heterocyclic nitrogen bases, e.g.pyridine; carboxylic acids, including lower alkanecarboxylic acids,e.g., AcOH; inorganic acids including HCl, HBr, HF, H₂SO₄ and the like;carboxylic acid anhydrides, including lower alkane acid anhydrides,e.g., acetic anhydride; cyclic, linear, or branched hydrocarbons,including cyclohexane, hexane, pentane, isopentane and the like, andmixtures of these solvents, such as purely organic solvent combinations,or water-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or not, prior to obtaining the finally desired compound.Structures resulting from carrying out steps from a transient startingmaterial, structures resulting from divergence from the describedmethod(s) at any stage, and structures forming starting materials underthe reaction conditions are all “intermediates” included in theinvention. Further, structures produced by using starting materials inthe form of a reactive derivative or salt, or produced by a compoundobtainable by means of the process according to the invention andstructures resulting from processing the compounds of the invention insitu are also within the scope of the invention.

New starting materials and/or intermediates, as well as processes forthe preparation thereof, are likewise provided by this invention.Starting materials of the invention, are either known, commerciallyavailable, or can be synthesized in analogy to or according to methodsthat are known in the art. Many starting materials may be preparedaccording to known processes and, in particular, can be prepared usingprocesses described in the examples. In synthesizing starting materials,functional groups may be protected with suitable protecting groups whennecessary. Protecting groups, their introduction and removal aredescribed above.

In synthesizing a compound of formulas I, II and III according to adesired procedure, the steps may be performed in an order suitable toprepare the compound, including a procedure described herein or by analternate order of steps described herein, and may be preceded, orfollowed, by additional protection/deprotection steps as necessary. Theprocedures may further use appropriate reaction conditions, includinginert solvents, additional reagents, such as bases (e.g., LDA, DIEA,pyridine, K₂CO₃, and the like), catalysts, and salt forms of the above.The intermediates may be isolated or carried on in situ, with or withoutpurification. Purification methods are known in the art and include, forexample, crystallization, chromatography (liquid and gas phase, and thelike), extraction, distillation, trituration, reverse phase HPLC and thelike. Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction. Synthetic chemistry transformations andprotecting group methodologies (protection and deprotection) useful insynthesizing the inhibitor compounds described herein are known in theart and include, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3^(rd)edition, John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); A.Katritzky and A. Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd)edition (2001); M. Bodanszky, A. Bodanszky, The Practice of PeptideSynthesis, Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne,Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2^(nd)edition, Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995).

In one embodiment, the present invention provides a method of making acompound of Formula I, the method comprising the step of reacting acompound 7

, wherein R¹, R² and R³ are as defined herein and X is a halogen, with aboronic acid having a general formula

wherein A¹, R⁴, R⁵ and n are as defined herein, to make a compound ofFormula I.

In another embodiment, the present invention provides a method of makinga compound of Formula II, the method comprising the step of reacting acompound 7

, wherein R¹, R² and R³ are as defined herein and X is a halogen, with aboronic acid having a general formula

wherein R^(4a), R^(4b) and R⁵ are as defined herein, to make a compoundof Formula II.

In another embodiment, the present invention provides a method of makinga compound of Formula III, the method comprising the step of reacting acompound 7

, wherein R¹, R² and R³ are as defined herein and X is a halogen, with aboronic acid having a general formula

wherein R^(4a), R^(4b), R⁷ and R⁸ are as defined herein, to make acompound of Formula III.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers including, without limitation, racemates and racemicmixtures, scalemic mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. All such isomeric forms ofthese compounds are expressly included in the present invention. Theoptical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof the invention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt.

The compounds of this invention may also be represented in multipletautomeric forms. The invention expressly includes all tautomeric formsof the compounds described herein.

The compounds may also occur in cis- or trans- or E- or Z-double bondisomeric forms. All such isomeric forms of such compounds are expresslyincluded in the present invention. All crystal forms of the compoundsdescribed herein are expressly included in the present invention.

Substituents on ring moieties (e.g., phenyl, thienyl, etc.) may beattached to specific atoms, whereby they are intended to be fixed tothat atom, or they may be drawn unattached to a specific atom, wherebythey are intended to be attached at any available atom that is notalready substituted by an atom other than H (hydrogen).

The present invention also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this inventioncan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

BIOLOGICAL EVALUATION

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and include those which increasebiological penetration into a given biological compartment (e.g., blood,lymphatic system, central nervous system), increase oralbioavailability, increase solubility to allow administration byinjection, alter metabolism and alter rate of excretion. By way ofexample, a compound of the invention may be modified to incorporate ahydrophobic group or “greasy” moiety in an attempt to enhance thepassage of the compound through a hydrophobic membrane, such as a cellwall.

Although the pharmacological properties of the compounds of theinvention (Formulas I, II and III) vary with structural change, ingeneral, activity possessed by compounds of Formulas I, II and III maybe demonstrated both in vitro as well as in vivo. Particularly, thepharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological in vitro assays, as well asin-vivo animal models.

The following assays were used to characterize the ability of compoundsof the invention to modulate the activity of human p38 enzyme, inhibitthe production of TNF-α and interleukin cytokines, including IL-1,IL-1-β, IL-6 and IL-8 and/or evaluate efficacy of a compound in an invivo animal model. Another assay, a cyclooxygenase enzyme (COX-1 andCOX-2) inhibition activity in vitro assay, can be used to characterizethe ability of compounds of the invention to inhibit COX-1 and/or COX-2.

Purified and Activated Recombinant Human p38α Aassay

Kinase Reaction Buffer: Kinase reaction buffer for p38α HTRF assaysconsists of 50 mM Tris-pH 7.5, 5 mM MgCl₂, 0.1 mg/mL BSA, 100 μM Na₃VO₄and 0.5 mM DTT.

HTRF Detection Buffer: HTRF detection buffer contains 100 mM HEPES-pH7.5, 100 mM NaCl, 0.1% BSA, 0.05% Tween-20, and 10 mM EDTA.

Serial Dilution of Compounds: Compounds were dissolved in 100% DMSO andserially diluted (3 fold, 10 point) in a polypropylene 96-wellmicrotiter plate (drug plate). The final starting concentration ofcompounds in the p38a enzymatic assays was 1 μM. Columns 6 and 12 (HIcontrols and LO controls respectively) in the drug plate were reservedas controls and contained only DMSO.Kinase Reaction: The p38α kinase reactions were carried out in apolypropylene 96-well black round bottom assay plate in total volume of30 μL kinase reaction buffer. Appropriate concentration of purified andactivated enzyme (recombinant human) was mixed with indicatedconcentration of ATP and 100 nM GST-ATF2-Avitag, in the presence orabsence (HI control) of Compound. See table below for actualconcentrations. In the absence of substrate, the background was measuredas LO control. The reaction was allowed to incubate for 1 hour at RT.Assay Reagent Concentrations: The final reagent concentrations were 1 nMp38α and 50 μM ATP. The Km for ATP of the enzyme was 103 μM, giving aratio of ATP concentration to Km of 0.49.HTRF Detection: The kinase reaction was terminated and phospho-ATF2 wasrevealed by addition of 30 μL of HTRF detection buffer supplemented with0.1 nM Eu-anti-pTP and 4 nM SA-APC. After 60 minutes incubation at roomtemperature, the assay plate was read in a Discovery Plate Reader. Thewells were excited with coherent 320 nm light and the ratio of delayed(50 ms post excitation) emissions at 620 nM (native europiumfluorescence) and 665 nm (europium fluorescence transferred toallophycocyanin—an index of substrate phosphorylation) was determined(Park et al, 1999).Data Analysis: The proportion of substrate phosphorylated in the kinasereaction in the presence of compound compared with that phosphorylatedin the presence of DMSO vehicle alone (HI control) was calculated usingthe formula: % control (POC)=(compound−average LO)/(average HI−averageLO)*100. Data (consisting of POC and inhibitor concentration in μM) wasfitted to a 4-parameter equation (y=A+((B−A)/(1+((x/C)^D))), where A isthe minimum y (POC) value, B is the maximum y (POC), C is the x(compound concentration) at the point of inflection and D is the slopefactor, using a Levenburg-Marquardt non-linear regression algorithm.

The inhibition constant (Ki) of the inhibitor was estimated from theIC₅₀ (compound concentration at the point of inflection C) using theCheng-Prussof equation: Ki=IC₅₀/(1+S/Km), where S is the ATP substrateconcentration, and Km is the Michaelis constant for ATP as determinedexperimentally. All results were expressed as the mean±the standarderror of the mean. Data acquisition and non-linear regression algorithmswere performed using Activity Base v5.2 and XL-fit software v4.1respectively. All data was archived using Activity Base v5.2 software.Data for Exemplary compounds in the human p38-alpha enzyme assay isprovided in Table 1.

Lipopolysaccharide-Activated PBMC CXytokine Production Assay

Isolation of PBMC

Test compounds were evaluated in vitro for the ability to inhibit theproduction of IL-1β, IL-6, and TNF-α by PBMC activated with bacteriallipopolysaccharide (LPS). Fresh leukocytes were obtained from a localblood bank, and peripheral blood mononuclear cells (PBMCs) were isolatedby density gradient centrifugation on Ficol-Paque Plus (Pharmacia).

Preparation of Test Compound Sstock Solutions

All reagents were prepared in RPMI 1640+10% v/v human AB serum+1×Pens/Strep/Glu (assay medium). Test compounds were dissolved in 100%DMSO and serially diluted in 96-well polypropylene round bottom microtiter plates (drug plate). Serial dilutions were then diluted 1:250 intoassay medium to a 4× working concentration. Compound serial dilutionswere half-log, 10 point titrations with a final starting concentrationof 1 μM.

Treatment of Cells with Test Compounds and Aactivation withLipopolysaccharide

LPS was prepared to a 4× concentration in assay medium. 100 μl of PBMC(1×10⁶ cells/ml) were plated in a 96-well polystyrene flat bottom microtiter tissue culture plate and incubated with 50 μl of 4× compoundserial dilution for 1 hour at 37° C., 5% CO₂ in a tissue cultureincubator. 50 μl 4× LPS or control was added and the plates wereincubated at 37° C., 5% CO₂ in a tissue culture incubator for 18 hours.The final DMSO concentration was 0.1%. The total volume was 200 μL. Thefinal LPS concentration was 100 ng/mL. After 18 hours culturesupernatants were removed and IL-1β, IL-6, and TNF-α presence in thesupernatants was quantified using MSD ECL based technology.

Cytokine Measurments

20 μL of culture supernatant were added to MSD plates, and incubated forone hour at room temperature. 20 μL of detection antibody diluted inantibody diluent (1 μg/mL), and 110 μL of 2× Read Buffer P was added,and incubated for one hour at RT. Electrochemiluminescence was measuredusing the SECTOR HTS Imager (MSD, Gaithersburg, Md.).

Data Aanalysis

Compound IC₅₀ values were calculated as follows: The proportion ofcytokine production in the presence of compound compared to the cytokineproduction in the presence of the DMSO vehicle alone (Hi control) wascalculated using the formula: Percent Control (POC)=(compound−averageLo)/(average Hi−average Lo)*100. To derive IC₅₀ values, POC was plottedagainst the Log of compound concentration (μM) and fitted to a4-parameter equation (y=A+((B−A)/(1+((x/C)^D))), where A is the minimumy (POC) value, B is the maximum y (POC), C is the concentration ofcompound at the inflection point, and D is the slope factor, using aLevenburg-Marquardt non-linear regression algorithm. Data acquisitionand non-linear regression were performed using Activity Base and XL-fitrespectively.

Compounds of the invention can also be shown to inhibit LPS-inducedrelease of IL-1β, IL-6 and/or IL-8 from PBMC by measuring concentrationsof IL-1β, IL-6 and/or IL-8 by methods well known to those skilled in theart. In a similar manner to the above described assay involving the LPSinduced release of TNF-α from PBMC, compounds of this invention can alsobe shown to inhibit LPS induced release of IL-1β, IL-6 and/or IL-8 fromPBMC by measuring concentrations of IL-1β, IL-6 and/or IL-8 by methodswell known to those skilled in the art. Thus, the compounds of theinvention may lower elevated levels of TNF-α, IL-1, IL-6, and IL-8levels. Reducing elevated levels of these inflammatory cytokines tobasal levels or below is favorable in controlling, slowing progression,and alleviating many disease states. All of the compounds are useful inthe methods of treating disease states in which TNF-α, IL-1β, IL-6, andIL-8 play a role to the full extent of the definition of TNF-α-mediateddiseases described herein.

Lipopolysaccharide-Activated THP1 Cell TNF Production Assay

THP1 cells were resuspended in fresh THP1 media (RPMI 1640, 10%heat-inactivated FBS, 1× PGS, 1× NEAA, plus 30 μM βME) at aconcentration of 1.5×10⁶ cells per mL. One hundred microliters of cellsper well were plated in a polystyrene 96-well tissue culture plate. 1.5micrograms per mL of bacterial LPS was prepared in THP1 media andtransferred to the first 11 columns of a 96-well polypropylene plate.Column 12 contained only THP1 media for the LO control. Compounds weredissolved in 100% DMSO and serially diluted 3 fold in a polypropylene96-well microtiter plate (drug plate). Columns 6 and 12 were reserved ascontrols (HI controls and LO controls respectively) and contained onlyDMSO. 10 μL of LPS followed by one microliter of inhibitor compound fromthe drug plate was transferred to the cell plate. The treated cells wereinduced to synthesize and secrete TNF-α in a 37° C. humidified incubatorwith 5% CO₂ for 3 hours. Fifty microliters of conditioned media wastransferred to a 96-well MULTI-ARRAY™ 96-well small spot plate—customcoated with MAB610 containing 100 μL of 2× Read Buffer P supplementedwith 0.34 nM AF210NA polyclonal Ab labeled with ruthenium(MSD-Sulfo-TAG™—NHS ester). After an overnight incubation at roomtemperature with shaking, the reaction was read on the Sector Imager™6000. A low voltage was applied to the ruthenylated TNF-α immunecomplexes, which in the presence of TPA (the active component in the ECLreaction buffer, Read Buffer P), resulted in a cyclical redox reactiongenerating light at 620 nm. The amount of secreted TNF-α in the presenceof AMG compounds compared with that in the presence of DMSO vehiclealone (HI control) was calculated using the formula: % control(POC)=(cpd−average LO)/(average HI−averageLO)*100. Data (consisting ofPOC and inhibitor concentration in μM) was fitted to a 4-parameterequation (y=A+((B−A)/(1+((x/C)^D))), where A is the minimum y (POC)value, B is the maximum y (POC), C is the x (cpd concentration) at thepoint of inflection and D is the slope factor) using aLevenburg-Marquardt non-linear regression algorithm.

Inhibition of TNF-α Induced IL-8 in 50% Human Whole Blood

Test compounds were evaluated in vitro for the ability to inhibit theproduction of secreted IL-8 by whole blood activated with TNF-α. Freshhuman whole blood was obtained from healthy, non-medicated volunteers insodium heparin tubes.

Compound Dilution—Assay Procedure

Test compounds are serially diluted 1:3 in DMSO and then diluted 1:250into R10 (RPMI 1640, 10% human serum AB, 1× pen/strep/glutamine) to the4× working concentration to be used in the assay. 100 ul heparinizedwhole blood is plated into wells of 96 well flat bottom plates. 50 ul ofeither 4× compound or DMSO control (Final DMSO concentration is 0.1%)are added to the appropriate wells. Plates are incubated for 1 hour at37 degrees Celsius. 50 ul of 4× TNF-α (4 nM TNF-α, for a finalconcentration of 1 nM) or control (media alone) is added to theappropriate wells (Total volume=200 ul). Plates are incubated overnight(16-18 hours). 100 ul of supernatant is collected and stored in 96-wellround bottom polypropylene plates at −80 degrees Celsius or assayedimmediately for IL-8.

Cytokine Measurement

Cytokines are measured on antibody (Ab) sandwich ECL based 96-welldetection plates. 20 ul of supernatant are added to plate and plate issealed and shaken at RT for 1 hour. 130 ul of detection Ab cocktail isadded and plates are sealed and shaken for 1 hour in the dark at RT.Plates are read on MSD Sector HTS instrument. Data are analyzed and IC₅₀values generated using Activity Base and Xl-fit programs. Data forexemplary compounds in the human p38-alpha enzyme assay is provided inTable 1.

Inhibition of LPS-Induced TNF-α Production Rats

LPS was diluted in PBS (100 μg per rat). Rats (n=6) were pretreated withvehicle or compound (0.03, 0.1, 0.3 and 1.0 mg/kg, PO) 60 minutes priorto the injection of LPS (100 μg per rat/IV, tail vein). Blood washarvested via decapitation 90 minutes following the administration ofLPS. Blood was centrifuged at 12,000 rpm for 12 minutes to obtainplasma. Plasma samples were stored at −80 C. TNF-α levels weredetermined by ELISA for treatment groups that received LPS. Rat TNF-αlevels were analyzed using rat TNF-α CytoSet kit from BiosourceInternational. ELISA was completed according to the manufacturer'sinstructions. The concentration of TNF-α was interpolated fromabsorbance using the standard curve generated. For each individualsample, the TNF value from the dilution series that fell in the mostlinear portion of the standard curve was chosen and used for dataanalysis. The limit of quantitation of the ELISA was 1,000 pg/mL.

Compounds of the invention may be shown to have anti-inflammatoryproperties in animal models of inflammation, including carageenan pawedema, collagen induced arthritis and adjuvant arthritis, such as thecarageenan paw edema model (C. A. Winter et al., Proc. Soc. Exp. Biol.Med., 111:544 (1962); K. F. Swingle, in R. A. Schemer and M. W.Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology,13(II):33, Academic, New York (1974) and collagen induced arthritis (D.E. Trentham et al., J. Exp. Med., 146:857 (1977); J. S. Courtenay,Nature (New Biol.), 283:666 (1980)).

Collagen-Iinduced Arthritis (CIA) Model in Rats

Porcine type II collagen (10 mg) was dissolved in 0.1N acetic acid (5mL) two days prior to use on a rotating plate in the refrigerator.Subsequently, collagen was emulsified 1:1 with Freund's incompleteadjuvant using an emulsification needle and glass syringes yielding afinal concentration of 1 mg/mL.

Disease was induced in each animal by intradermal injection ofemulsified collagen in IFA at 10 different sites (100 μL per site) overthe back. The clinical onset of arthritis varied between days 10 to 12as indicated by hind paw swelling and ambulatory difficulties. At onset(defined as Day 0), rats were randomized to treatment groups and therapywas initiated with drug or vehicle control as noted in table above. Ratswere treated for 7 days and were sacrificed on Day 8. Paw swelling andother measurements of efficacy is described Schett et al (Schett et al.Arthritis and Rheum. 52:1604 (2005).

Cyclooxygenase Enzyme Activity Assay

The human monocytic leukemia cell line, THP-1, differentiated byexposure to phorbol esters expresses only COX-1; the human osteosarcomacell line 143B expresses predominantly COX-2. THP-1 cells are routinelycultured in RPMI complete media supplemented with 10% FBS and humanosteosarcoma cells (HOSC) are cultured in minimal essential mediasupplemented with 10% fetal bovine serum (MEM-10% FBS); all cellincubations are at 37° C. in a humidified environment containing 5% CO₂.

COX-1 Assay

In preparation for the COX-1 assay, THP-1 cells are grown to confluency,split 1:3 into RPMI containing 2% FBS and 10 mM phorbol 12-myristate13-acetate (TPA), and incubated for 48 h on a shaker to preventattachment. Cells are pelleted and resuspended in Hank's Buffered Saline(HBS) at a concentration of 2.5×10⁶ cells/mL and plated in 96-wellculture plates at a density of 5×10⁵ cells/mL. Test compounds arediluted in HBS and added to the desired final concentration and thecells are incubated for an additional 4 hours. Arachidonic acid is addedto a final concentration of 30 mM, the cells incubated for 20 minutes at37° C., and enzyme activity determined as described below.

COX-2 Assay

For the COX-2 assay, subconfluent HOSC are trypsinized and resuspendedat 3×10⁶ cells/mL in MEM-FBS containing 1 ng human IL-lb/mL, plated in96-well tissue culture plates at a density of 3×10⁴ cells per well,incubated on a shaker for 1 hour to evenly distribute cells, followed byan additional 2 hour static incubation to allow attachment. The media isthen replaced with MEM containing 2% FBS (MEM-2%FBS) and 1 ng humanIL-lb/mL, and the cells incubated for 18-22 h. Following replacement ofmedia with 190 mL MEM, 10 mL of test compound diluted in HBS is added toachieve the desired concentration and the cells incubated for 4 h. Thesupernatants are removed and replaced with MEM containing 30 mMarachidonic acid, the cells incubated for 20 minutes at 37° C., andenzyme activity determined as described below.

COX Activity Determined

After incubation with arachidonic acid, the reactions are stopped by theaddition of 1N HCl, followed by neutralization with 1 N NaOH andcentrifugation to pellet cell debris. Cyclooxygenase enzyme activity inboth HOSC and THP-1 cell supernatants is determined by measuring theconcentration of PGE₂ using a commercially available ELISA (Neogen#404110). A standard curve of PGE₂ is used for calibration, andcommercially available COX-1 and COX-2 inhibitors are included asstandard controls. Various compounds of the invention may be shown toinhibit the COX-1 and/or COX-2 activity.

INDICATIONS

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of inflammation, pro-inflammatorycytokines levels including, without limitation, TNF, IL-1, IL-2, IL-6and/or IL-8, and disease associated therewith. The compounds of theinvention have p38 kinase modulatory activity. In one embodiment of theinvention, there is provided a method of treating a disorder related tothe activity of p38 enzyme in a subject, the method comprisingadministering to the subject an effective dosage amount of a compound ofa compound of Formulas I, II or III.

Accordingly, the compounds of the invention would be useful in therapyas anti-inflammatory agents in treating inflammation, or to minimizedeleterious effects of p38. Based on the ability to modulatepro-inflammatory cytokine production, the compounds of the invention arealso useful in treatment and therapy of cytokine-mediated diseases.Particularly, these compounds can be used for the treatment ofrheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma,uveitis, acute or chronic myelogenous leukemia, pancreatic β celldestruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis,inflammatory bowel disease, adult respiratory distress syndrome (ARDS),psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis,anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia,Reiter's syndrome, type I diabetes, type II diabetes, bone resorptiondiseases, graft vs. host reaction, Alzheimer's disease, stroke,myocardial infarction, ischemia reperfusion injury, atherosclerosis,brain trauma, multiple sclerosis, cerebral malaria, sepsis, septicshock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3,cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses orherpes zoster infection, or any combination thereof, in a subject.

An example of an inflammation related disorder is (a) synovialinflammation, for example, synovitis, including any of the particularforms of synovitis, in particular bursal synovitis and purulentsynovitis, as far as it is not crystal-induced. Such synovialinflammation may for example, be consequential to or associated withdisease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis orarthritis deformans. The present invention is further applicable to thesystemic treatment of inflammation, e.g. inflammatory diseases orconditions, of the joints or locomotor apparatus in the region of thetendon insertions and tendon sheaths. Such inflammation may be, forexample, consequential to or associated with disease or further (in abroader sense of the invention) with surgical intervention, including,in particular conditions such as insertion endopathy, myofascialesyndrome and tendomyosis. The present invention is further applicable tothe treatment of inflammation, e.g. inflammatory disease or condition,of connective tissues including dermatomyositis and myositis.

The compounds of the invention can also be used as active agents againstsuch disease states as arthritis, atherosclerosis, psoriasis,hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals,ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacterrelated diseases, fractures, cat scratch fever, rubeosis, neovascularglaucoma and retinopathies such as those associated with diabeticretinopathy or macular degeneration.

The compounds of the invention are also useful in the treatment ofdiabetic conditions such as diabetic retinopathy and microangiopathy.

The compounds of the present invention are also useful for treatingankylosing spondylitis, inflammatory bowel disease, inflammatory pain,ulcerative colitis, Crohn's disease, asthma, chronic obstructivepulmonary disease, myelodysplastic syndrome, endotoxic shock, chronichepatitis C or a combination thereof.

Thus, the present invention provides methods for the treatment of p38protein kinase-associated disorders, comprising the step ofadministering to a subject, including human subjects, prophylacticallyor therapeutically, at least one compound of the Formula I or of FormulaII in an amount effective therefore. Other therapeutic agents such asthose described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention. The present invention also provides for a method for treatingatopic dermatitis by administration of a therapeutically effectiveamount of a compound of the present invention to a patient, whether ornot in need of such treatment.

In yet another embodiment, the compounds are useful for decreasing thelevel of, or lowering plasma concentrations of one or more of TNF-α,IL-β, IL-6 and IL-8 in a subject, including human subjects, generally amammal and typically a human.

In yet another embodiment, the compounds are useful for treating a paindisorder in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulasI, II or III.

In yet another embodiment, the compounds are useful for treatingdiabetes in a subject, including human subjects, by administering to thesubject an effective dosage amount of a compound according to formulas Ior II, to produce a glucagon antagonist effect.

In yet another embodiment, the compounds are useful for decreasingprostaglandin production in a subject, including human subjects, byadministering to the subject an effective dosage amount of a compoundaccording to formulas I, II or III.

In yet another embodiment, the compounds are useful for decreasingcyclooxygenase enzyme activity in a subject, including human subjects,by administering to the subject an effective amount of a compoundaccording to formulas I, II or III.

In yet another embodiment, the cyclooxygenase enzyme is COX-2.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating TNF-α, IL-1, IL-6, and IL-8 mediated diseases,cancer, and/or hyperglycemia with the compounds and/or compositions ofthis invention depends on a variety of factors, including the age,weight, sex and medical condition of the subject, the type of disease,the severity of the disease, the route and frequency of administration,and the particular compound employed. Thus, the dosage regimen may varywidely, but can be determined routinely using standard methods. A dailydose of about 0.001 mg/kg to 500 mg/kg, advantageously between about0.01 and about 50 mg/kg, more advantageously about 0.01 and about 30mg/kg, even more advantageously between about 0.1 and about 10 mg/kg,and should be useful for all methods of use disclosed herein. The dailydose can be administered in one to four doses per day.

While it may be possible to administer a compound alone, the compound ofFormulas I, II or III is normally administered as an activepharmaceutical ingredient (API) in a composition comprising othersuitable and pharmaceutically acceptable excipients. This admixture istypically referred to as a pharmaceutical composition. This compositionshould be pharmaceutically acceptable. In another embodiment, theinvention provides a pharmaceutical composition comprising a compound ofthe present invention in combination with a pharmaceutically acceptableexcipient. Pharmaceutical excipients generally include diluents,carriers, adjuvants and the like (collectively referred to herein as“excipient” materials) as described herein, and, if desired, otheractive ingredients. A pharmaceutical composition of the invention maycomprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectiveamount of the compound is typically that amount capable of bring about adesired physiological effect in the subject. An effective dosage amountof a compound of the invention may constitute administering to thesubject one or more than one individual dosage units of thepharmaceutically acceptable composition comprising said compound. Forexample, where two or more unit dosages of a pharmaceutical composition,such as a tablet, pill, capsule, liquid, suspension and the like, may berequired to administer an effective amount of the compound, then theeffective dosage amount of the API is less than the effective amount ofthe API. Thus, an effective dosage amount may include an amount lessthan, equal to or greater than an effective amount of the compound. Asuitable pharmaceutically acceptable composition, such as a powder, aliquid and the like, may exist in which the effective amount of thecompound is administered by administering a portion of the compositionand requiring the subject to take multiple doses over a specified periodof time.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of API from about 1 to 2000 mg, advantageously fromabout 1 to 500 mg, and typically from about 5 to 150 mg. A suitabledaily dose for a human or other mammal may vary widely depending on thecondition of the patient and other factors, but, once again, can bedetermined using routine methods and practices.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more “excipients” appropriate to the indicatedroute of administration. If orally administered on a per dose basis, thecompounds may be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol, to form the finalformulation. For example, the compound(s) and excipient(s) may betableted or encapsulated by known and accepted methods for convenientadministration. Examples of suitable formulations include, withoutlimitation, pills, tablets, soft and hard-shell gel capsules, troches,orally-dissolvable forms and delayed or controlled-release formulationsthereof. Particularly, capsule or tablet formulations may contain one ormore controlled-release agents, such as hydroxypropylmethyl cellulose,as a dispersion with the active compound(s).

In the case of psoriasis and other skin conditions, it may be preferableto apply a topical preparation of compounds of this invention to theaffected area two to four times a day. Formulations suitable for topicaladministration include liquid or semi-liquid preparations suitable forpenetration through the skin (e.g., liniments, lotions, ointments,creams, pastes, suspensions and the like) and drops suitable foradministration to the eye, ear, or nose. A suitable topical dose ofactive ingredient of a compound of the invention is 0.1 mg to 150 mgadministered one to four, preferably one or two times daily. For topicaladministration, the active ingredient may comprise from 0.001% to 10%w/w, e.g., from 1% to 2% by weight of the formulation, although it maycomprise as much as 10% w/w, but preferably not more than 5% w/w, andmore preferably from 0.1% to 1% of the formulation.

When formulated in an ointment, the active ingredients may be employedwith either paraffinic or a water-miscible ointment base. Alternatively,the APIs may be formulated in a cream with an oil-in-water cream base.If desired, the aqueous phase of the cream base may include, for exampleat least 30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof. The topical formulation may desirably include acompound, which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include DMSO and related analogs.

The compounds of this invention can also be administered by transdermaldevice. Preferably transdermal administration will be accomplished usinga patch either of the reservoir and porous membrane type or of a solidmatrix variety. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier, it may comprise a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier, which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make-up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase, which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the present invention include, for example, Tween 60, Span 80,cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus, the cream should preferably bea non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters may be used.These may be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (i.e.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The API may also be administered by injection as a composition withsuitable carriers including saline, dextrose, or water. The dailyparenteral dosage regimen will be from about 0.1 to about 30 mg/kg oftotal body weight, preferably from about 0.1 to about 10 mg/kg, and morepreferably from about 0.25 mg to 1 mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable non-irritating excipient such as cocoabutter and polyethylene glycols that are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment, the present invention providesthe use of a medicament for the treatment of inflammatory conditions,including RA, psoriasis, psoriatic arthritis, pain, COPD, Crohn'sdisease, and other indications described herein.

In yet another embodiment, there is provided a method of manufacturing amedicament for the treatment of inflammation, the method comprisingcombining an amount of a compound according to Formulas I or II with apharmaceutically acceptable carrier to manufacture the medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of TNF-α, IL-1, IL-6, and IL-8mediated diseases, cancer, and/or hyperglycemia.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I and II may also be administered sequentially with knownanti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The compounds of the invention may also be used in co-therapies withanti-neoplastic agents such as other kinase inhibitors, including CDKinhibitors, TNF inhibitors, metallomatrix proteases inhibitors (MMP),COX-2 inhibitors including celecoxib, rofecoxib, parecoxib, valdecoxib,and etoricoxib, NSAID's, SOD mimics or α_(v)β₃ inhibitors.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein A¹ is CR⁴ or N; Bis O, S or N—CN; R¹ is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₁₀-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl and C₄₋₁₀-cycloalkenyl optionally comprising 1-4heteroatoms selected from N, O and S and optionally substituted with 1-5substituents of R⁹, or R¹ is a 3-8 membered monocyclic or 6-12 memberedbicyclic ring system, said ring system formed of carbon atoms optionallyincluding 1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic,said heteroatoms selected from 0, N, or S, wherein said ring system isoptionally substituted independently with 1-5 substituents of R⁹; R² isH, halo, haloalkyl, NO₂, CN, OR⁷, SR⁷, NR⁷R⁷, NR⁷R⁸, C(O)R⁷,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with one or more substituents ofR⁹; R³ is CN, C(O)R⁷, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl orC₃₋₈-cycloalkyl, each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyland C₃₋₈-cycloalkyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of R⁹; eachR⁴, independently, is H, halo, haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ orC₁₋₁₀-alkyl, the C₁₋₁₀-alkyl optionally comprising 1-4 heteroatomsselected from N, O and S and optionally substituted with 1-5substituents of R⁹; R⁵ is R⁷, NR⁷R⁷, NR⁷R⁸, OR⁷, SR⁷, OR⁸, SR⁸, C(O)R⁷,C(NCN)R⁷, C(O)R⁸, C(NCN)R⁸, C(O)C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)C(O)R⁸,OC(O)R⁸, COOR^(S), C(O)NR⁷R⁷, C(O)NR⁷R⁸, OC(O)NR⁷R⁸, NR⁷C(O)R⁷,NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷,S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸; each R⁷, independently, is H, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl or C₄₋₁₀-cycloalkenyl, each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl andC₄₋₁₀-cycloalkenyl optionally comprising 1-4 heteroatoms selected fromN, O and S and optionally substituted with 1-5 substituents of NR⁸R⁹,NR⁹R⁹, OR⁸, SR⁸, OR⁹, SR⁹, C(O)R⁸, OC(O)R⁸, COOR⁸, C(O)R⁹, OC(O)R⁹,COOR⁹, C(O)NR⁸R⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁸, NR⁹C(O)R⁹, NR⁹C(O)NR⁸R⁹,NR⁹C(O)NR⁹R⁹, NR⁹(COOR⁸), NR⁹(COOR⁹), OC(O)NR⁸R⁹, OC(O)NR⁹R⁹, S(O)₂R⁸,S(O)₂NR⁸R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂NR⁸R⁹, NR⁹S(O)₂NR⁹R⁹,NR⁹S(O)₂R⁸, NR⁹S(O)₂R⁹, R⁸ or R⁹; R⁸ is a partially or fully saturatedor fully unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic, or7-14 membered tricyclic ring system, said ring system formed of carbonatoms optionally including 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms selected from 0, N, or S, and wherein each ring of said ringsystem is optionally substituted independently with 1-5 substituents ofR⁹, oxo, NR⁹R⁹, OR⁹, SR⁹, C(O)R⁹, COOR⁹, C(O)NR⁹R⁹, NR⁹C(O)R⁹,NR⁹C(O)NR⁹R⁹, OC(O)NR⁹R⁹, S(O)₂R⁹, S(O)₂NR⁹R⁹, NR⁹S(O)₂R⁹, or apartially or fully saturated or unsaturated 5-6 membered ring of carbonatoms optionally including 1-3 heteroatoms selected from 0, N, or S, andoptionally substituted independently with 1-3 substituents of R⁹;alternatively, R⁷ and R⁸ taken together form a saturated or partially orfully unsaturated 5-6 membered monocyclic or 7-10 membered bicyclic ringof carbon atoms optionally including 1-3 heteroatoms selected from 0, N,or S, and the ring optionally substituted independently with 1-5substituents of R⁹; R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14membered tricyclic ring system, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom 0, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxy,ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl; and n is 0, 1 or
 2. 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein A¹ is CR⁴ and R⁴ is H,F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN, C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with 1-5 substituents of R⁹; and R² is H, halo,haloalkyl, NO₂, CN, OR⁷, NR⁷R⁷ or C₁₋₁₀-alkyl.
 3. The compound of claim2, or a pharmaceutically acceptable salt thereof, wherein R¹ isC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl or C₃₋₁₀-cycloalkyl, each ofthe C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl and C₃₋₁₀-cycloalkyloptionally comprises 1-4 heteroatoms selected from N, O and S andoptionally substituted with 1-5 substituents of R⁹.
 4. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ isNR⁷R⁷, NR⁷R⁸, C(O)R⁷, C(O)R⁸, C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷,NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸, NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷,S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸, NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ orNR⁷S(O)₂R⁸.
 5. The compound of claim 4, or a pharmaceutically acceptablesalt thereof, wherein R⁸ is a ring selected from phenyl, naphthyl,pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxazinyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl, wherein said ring is optionallysubstituted independently with 1-3 substituents of R⁹.
 6. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isphenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl, pyrazinyl,quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl,furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxazolinyl,isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl, indolyl, indolinyl,isoindolyl, benzofuranyl, dihydrobenzofuranyl, benzothiophenyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, benzimidazolyl,piperidinyl, pyranyl, cyclopropyl, cyclobutyl or cyclohexyl, each ofwhich is optionally substituted.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R³ is CN, C(O)R⁷,C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl or C₁₋₄-alkyl-amino-C₁-alkyl orC₁₋₁₀-dialkylaminoC₁₋₄-alkyl-.
 8. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein A¹ is CR⁴; B is O; R¹is phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, pyridazinyl,pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl,thiophenyl, furyl, tetrahydrofuryl, pyrrolyl, tetrahydropyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,oxazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, isothiazolyl,indolyl, indolinyl, isoindolyl, benzofuranyl, dihydrobenzofuranyl,benzothiophenyl, benzisoxazolyl, benzopyrazolyl, benzothiazolyl,benzimidazolyl, piperidinyl, pyranyl, cyclopropyl, cyclobutyl orcyclohexyl, each of which is optionally substituted independently with1-3 substituents of R⁹; R² is H, halo, haloalkyl or C₁₋₁₀-alkyl; R³ isCN, C(O)R⁷, C₁₋₄-alkylC(O)R⁷, methyl, ethyl, propyl, isopropyl,cyclopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl orC₁₋₄-alkyl-amino-C₁₋₄-alkyl or C₁₋₁₀-dialkylaminoC₁₋₄-alkyl-; each R⁴,independently, is H, F, Cl, Br, CF₃, —OCF₃, C₂F₅, —OC₂F₅, —O—C₁₋₆-alkyl,—C₁₋₄-alkyl-O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —C₁₋₄-alkyl-S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C₁₋₄-alkyl-NH—C₁₋₆-alkyl,—C₁₋₃-alkyl-N(C₁₋₄-alkyl)₂, NO₂, NH₂, CN or C₁₋₁₀-alkyl, the C₁₋₁₀-alkyloptionally substituted with 1-5 substituents of R⁹; R⁵ is NR⁷R⁷, NR⁷R⁸,C(O)NR⁷R⁷, C(O)NR⁷R⁸, NR⁷C(O)R⁷, NR⁷C(O)R⁸, NR⁷C(O)NR⁷R⁷, NR⁷C(O)NR⁷R⁸,NR⁷(COOR⁷), NR⁷(COOR⁸), S(O)₂R⁷, S(O)₂R⁸, S(O)₂NR⁷R⁷, S(O)₂NR⁷R⁸,NR⁷S(O)₂NR⁷R⁸, NR⁷S(O)₂R⁷ or NR⁷S(O)₂R⁸; each R⁷, independently, is H,C₁₋₁₀-alkyl or C₃₋₁₀-cycloalkyl, wherein the C₁₋₁₀-alkyl andC₃₋₁₀cycloalkyl optionally comprising 1-4 heteroatoms selected from N, Oand S and optionally substituted with 1-3 substituents of R⁹; R⁸ is aring selected from phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl,pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl,isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzopyrazolyl, benzothiazolyl, tetrahydrofuranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein said ringis optionally substituted independently with 1-3 substituents of R⁹; R⁹is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cyclo alkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a saturated or partially or fully unsaturated 5-8 memberedmonocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ringsystem, said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from 0, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and each ring ofsaid ring system is optionally substituted independently with 1-3substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxy,ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl,tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine,propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl orphenyl; and n is 0 or
 1. 9. The compound of claim 1, or apharmaceutically acceptable salt thereof, selected from:N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;3-(1-(2,4-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-N-3-isoxazolyl-4-methylbenzamide;N-cyclopropyl-3-(1-(2,4-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-5-fluoro-4-methylbenzamide;N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;3-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-5-fluoro-4-methylbenzamide;and3-(1-(2,6-difluorophenyl)-7-ethyl-6-oxo-6,7-dihydro-1H-pyrazolo[3,4-b]pyrazin-5-yl)-N-3-isoxazolyl-4-methylbenzamide.10. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable excipient.
 11. Apharmaceutical composition comprising a compound according to claim 9and a pharmaceutically acceptable excipient.
 12. A method of preparing acompound according to claim 1, the method comprising the step ofreacting a compound of formula 7

wherein R¹, R² and R³ are as defined in claim 1 and X is a halogen, witha boronic acid having a general formula

wherein A¹, R⁴, R⁵ and n are as defined in claim 1, to make a compoundof claim 1.